bluuebunny/crossref_metadata_2025 huggingface dataset:
A new approach to the problem of docking two molecules: The ellipsoid algorithm
Authors: Billeter M. , Havel T. F. , Kuntz I. D.
Published: December 2004

A recently developed method of constrained optimization, known as the ellipsoid algorithm, is explored as a tool for determining sterically acceptable interactions between two molecules. These interactions are described by constraints on intermolecular distances. Upper distance bounds between specific pairs of atoms, one in the ligand and one in the enzyme, were used in two different types of docking problems. In the first type, knowledge of a small set of well‐defined upper distance constraints was assumed, e.g., specific information about hydrogen bonds or experimentally determined atom–atom distances. The second approach assumes only knowledge of the location of the binding site of one of the molecules, but nothing about how the second, typically small, molecule is packed into this site. In this case, a set of upper distance bounds was used one at a time to explore systematically all possible ways of packing the ligand into the site. In all applications, van der Waals repulsions were used to define a lower distance bound for each atom pair. To specify the relative orientation of the two molecules, a new set of variables had to be introduced. They enable us to represent the set of all possible rotations in a vector space as required by the ellipsoid algorithm. Consequently, in contrast to the usual Euler angles, they assure additivity, so that the result of multiple changes of the variables is not sensitive to the order in which they are performed. In addition to the six degrees of freedom involved in docking rigid objects, conformational flexibility can be explicitly included in the individual molecules. Applications discussed include the docking of two macromolecules and the formation of an enzyme–inhibitor complex. For each constraint set tested, ten randomly chosen starting structures were optimized. The time for each of the runs was between 3 min and 1.3 h on a VAX 750 or a Microvax II; in larger problems, the time is spent primarily in van der Waals checking. The advantages of the ellipsoid algorithm compared to other methods are its robustness with respect to local minima, and the relatively small amounts of computer time and memory that it needs. A final discussion compares this method to some other docking methods, including distance geometry and the matching of molecular surfaces.
Nmr studies on the presence of domain structures in polysaccharides
Authors: Lacelle Serge , Gerstein Bernard C.
Published: December 2004

A variety of nmr transient techniques demonstrate the absence of domain structures in powders of α‐ and β‐cyclodextrins, dextran B512F, and their “deuterated” analogs where deuterium replaces exchangeable protons. Cyclodextrins and dextran are inferred to be homogeneously ordered and disordered one‐phase systems, respectively. We show how erroneous results concerning the presence and sizes of rigid and mobile domains can be reached from the interpretations of two‐component free induction decays and spin–lattice relaxation behavior of polysaccharides. In our approach, we have measured 1H free induction decays and lineshapes, and 1H spin–lattice and dipolar relaxation times, in addition to using Goldman–Shen experiments and 13C cross‐polarization magic‐angel sample spinning. Self‐consistent nmr results are suggested as essential means to corroborate conclusions concerning domain structures in biopolymers.
β‐Turns in serine‐containing linear and cyclic models
Authors: Hollósi M. , Kövér K. E. , Holly S. , Fasman G. D.
Published: December 2004

Tetrapeptides, Cbz‐Gly‐X‐Y‐Gly‐OSt (1–4)—as well as cyclic systems, cyclo[NH‐(CH2)n‐CO‐Gly‐Ser(OX)‐Ser(OX)‐Gly] (5 and 6; n = 4 and 2, X = But or H), have been synthesized in order to compare the CD spectrum of linear and cyclic β‐turn models containing either a protected or a free hydroxyl of the serine residue. In extremely dilute cyclohexane solution the linear models Cbz‐Gly‐Ser‐Y‐Gly‐OSt (1–3a) show class B spectra with very strong positive bands, contrary to other members of the series. Based on 200‐MHz 1H nuclear overhauser enhancement and Fourier transform ir studies, Cbz‐Gly‐Ser‐Ser(OBut)‐Gly‐OSt (3a) in dilute chloroform solution assumes a distorted type II β‐turn conformation fixed by an extended system of intramolecular H bonds. As evidenced by 1H‐nmr and FT‐IR experiments, the cyclic model cyclo[NH‐(CH2)4‐CO‐Gly‐Ser(OBut)‐ Ser(OBut)‐Gly] (5a) in a 1 : 1 mixture of (CD3)2SO‐CDCl3 is also characterized by a type II β‐turn encompassing the Ser3(OBut)‐Gly4 sequence. In water, a class B pattern was measured for this model, in good agreement with theoretical and experimental studies that show that type II β‐turns are generally characterized by class B spectra. In the protected and free OH cyclic models, cyclo[NH‐(CH2)2‐CO‐Gly‐Ser(OX)‐Ser(OX)‐Gly] (5b and 6b, X = But or H) distortions of the peptide backbone due to the loss of two CH2 groups result in the appearance of CD spectra characterized by a strong negative band near 200 nm, interpreted as a sign of the lack of β‐turn structures in these models. This observation, together with other CD data discussed in this paper, clearly show that the CD of serine‐containing β‐turn sequences strongly depends on long‐range backbone and local side‐chain interactions.
Thermodynamic models for water–protein sorption hysteresis
Authors: Bryan William P.
Published: December 2004

Sorption isotherms of water by proteins show hysteresis that appears to be due to interactions at the molecular level. Four thermodynamically consistent models for this irreversible process are presented. Hysteresis could be the result of slow, incomplete conformational changes occurring upon addition and removal of water. Conformational hysteresis would occur if a number of different conformations, each corresponding to a local free energy minimum, could be present at each pressure of water vapor. Hysteresis might result from an incomplete process of intermolecular phase annealing. Finally, hysteresis might be due to incomplete phase change if two different protein phases are present. Experimental tests for these models are presented. Further study should lead to more insight into the effects of the presence of water on protein conformation and dynamics.
Anion effects on equilibria and kinetics of the disorder–order transition of κ‐carrageenan
Authors: Austen Kevan R. J. , Goodall David M. , Norton Ian T.
Published: December 2004

The effect of a number of tetramethylammonium salts on the equilibria and kinetics of the disorder to order transition in the polysaccharide κ‐carrageenan have been investigated. Data from the temperature dependence of optical rotation show that anion stabilization of the ordered form follows the lyotropic series I− > Br− > NO > Cl− > F−. Stopped‐flow polarimetry was used to study the kinetics of conformational ordering following a rapid increase in salt concentration. The transition to the new equilibrium position was shown to be biphasic for all of the tetramethylammonium salts studied. The rate equation for the fast phase and the temperature dependence of the observed forward rate constant accord with a cooperative dimerization process. Activation parameters for helix nucleation, ΔH* and ΔS*, vary with both salt concentration and (at constant ionic strength) the anion type, increasing through the lyotropic series from I− to F−. The slow phase shows second‐order kinetics, and is interpreted as further stabilization of the ordered form either through limited aggregation or annealing. The rate constant for the slow phase also follows the lyotropic series. Thus we have shown that both the growth and nucleation processes are anion dependent.
Electron microscopy of beaded agarose gels
Authors: Attwood T. K. , Nelmes B. J. , Sellen D. B.
Published: December 2004

Electron microscopy has been carried out on sections of beaded agarose with a wide range of thicknesses, and the results have been analyzed by means of stereological theory using computer graphics. The results agree with a randomly orientated system in which, for 4% gels, the mean molecular weight per unit length of the fiber system is 110 kg mol−1 nm−1, and the number average interjunction length is 37 nm, with an asymmetrical distribution resembling a Maxwell‐Boltzmann distribution. The spatial distribution of the structure is not uniformly random and there seem to be mi microvoids.
Induced CD provides evidence for helical solution conformation in cellulosic chains
Authors: Ritcey Anna M. , Gray Derek G.
Published: December 2004

Evidence for a helical contribution to the conformation of methylcellulose in dilute solution is given by CD measurements. Congo red binds to methylcellulose in dilute aqueous solution and becomes optically active. The shape of the induced CD spectra is as predicted by exciton coupling for a helical arrangement of chromophores. The magnitude of the induced CD changes reversibly with temperature, decreasing upon heating. The dimer analogue of the polymer, prepared by acid methanolysis, does not show this effect. These observations suggest that the induced optical activity reflects the conformational dissymmetry of the polymer. Analogous experiments with the cellulose oligomers (cellotriose through cellohexaose) show that five anhydroglucose units are necessary before asymmetry is induced upon dye binding.
Base sequence effects in double‐helical DNA. II. Configurational statistics of rodlike chains
Authors: Maroun Rachid C. , Olson Wilma K.
Published: December 2004

Matrix generator techniques have been adapted to account for precise structural features of the nucleotide repeating unit and to translate the primary sequence of DNA base pairs into three‐dimensional structures. Chains have been constructed to reflect the local sequence‐dependent differences of bending and twisting of adjacent residues and various overall chain properties, including the average unperturbed moments of the end‐to‐end vector r and the mean angular orientation (〈γ〉 between base pair normals, 〈ϕ1〉 between long axes, and 〈ϕ2〉 between short axes) of terminal chain residues, have been computed. The chain backbone is treated implicitly in terms of the spatial fluctuations of successive base pairs. Motions are limited to low‐energy perturbations of the standard B‐DNA helix. Approximate potential energy schemes are used to represent the rules governing the patterns of local base–base morphology and flexibility. Theoretical predictions are compared with experimental observations at both the local and the macro‐molecular level. Initial applications are limited to the rodlike poly(dA) · poly(dT) and poly(dG) · poly(dC) helices. The former duplex is found to be more compressed and the latter more extended than random‐sequence DNA of the same chain length. The flexibility of the duplexes as a whole is described in terms of the average higher moments of the displacement vector ρ = r ‐ 〈r〉 and the likelihood of chain cyclization is estimated from the three‐dimensional Hermite series expansions of the displacement tensors. Emphasis is placed on theoretical methodology and the practical relevance of the calculated chain moments to observed physical properties.
Collapse of a polypeptide chain as a result of the intramolecular formation of antiparallel β‐sheets
Authors: Tilstra Luanne F. , Mattice Wayne L.
Published: December 2004

The folded nature of an intramolecular antiparallel β‐sheet suggests that the introduction of this structure into a statistical coil might be accompanied by a contraction of the chain. The magnitude of the contraction, and the conditions that produce the maximum contraction, have been assessed by the combination of generator matrices with an earlier formulation for the configuration partition function. The results show that the mean square dimensions do indeed pass through a minimum upon the transition from a statistical coil to an antiparallel β‐sheet. The depth of the minimum is relatively insensitive to the values of δ and τ, provided the assignments are within the physically sensible range. (The borders of the ordered region are assumed to be of higher energy than the interior.) In contrast with the depth of the minimum, the β‐sheet content that produces the minimum is quite sensitive to plausible variation in δ and τ. A much greater collapse of the chain can be produced by antiparallel β‐sheet formation than that found in the course of the helix–coil transition. The collapse may cause the volume pervaded by the chain to come within an order of magnitude of the volume characteristic of the globular state.
Conformational studies of N‐acetyl‐N′‐methylamide derivatives of α‐aminobutyric acid, norvaline, and valine. II. Conformational energy calculations and comparison with experimental results
Authors: Abe Akihiro , Yamazaki Toshimasa
Published: December 2004

Conformational analyses on a series of dipeptides CH3—C*O—NH—CH(R)—C*O—HN—CH3 with side chains such as R = CH2CH3, CH2CH2CH3, and CH(CH3)2 are described. Calculations were carried out by using semiempirical potential energy functions of Brant et al. The results were compared with those reported by Vásquez et al. and Chuman et al., who employed the ECEPP program in their analyses. The averages of the vicinal coupling constant J and the side‐chain conformer fractions p(χ1) and p(χ2)′ were estimated therefrom for preferred conformations. The characteristic features of the experimental observations derived from the 1H‐nmr measurements are reasonably well reproduced by these calculations.
Stacking and edge‐to‐edge associations of antitumoral ellipticine derivatives are controlled in solution by interactions involving their nitrogen sites
Authors: Sizun P. , Auclair C. , Lescot E. , Paoletti C. , Perly B. , Fermandjian S.
Published: December 2004

1H chemical shift dilution experiments on the cytotoxic drugs 2‐methylellipticinium 1 and its methylated still active analogues 2,6‐dimethylellipticinium 2 and 1,2‐dimethylellipticinium 3 indicate that the three chromophores autoassociate in dimers, trimers, and larger aggregates. The results suggest that the same chromophores are both stacked via transannular π interactions and associated edge to edge via interactions involving the nitrogen atoms such that layer structures similar to those observed in crystals could be formed at high concentration. Substitution with a methyl group on the N6 position or the C1 position near the N, results in analogues displaying an association constant significantly reduced when compared to parent compound 1. This decrease is attributed to the loss or strength weakening of the forces involving nitrogen atoms rather than to the steric influence of the methyl substituents on the stacking of chromophores. The results are further discussed in terms of the various modes of binding of the ellipticines to DNA.
The ligation and flexibility of four‐arm DNA junctions
Authors: Petrillo Mary L. , Newton Colin J. , Cunningham Richard P. , Ma Rong‐Ine , Kallenbach Neville R. , Seeman Nadrian C.
Published: December 2004

Four‐arm DNA branched junctions are stable analogs of Holliday recombination intermediates, constructed from oligonucleotides. The conformational flexibility of junctions can be estimated by ligating them together and determining the set of closed macrocyclic products that are obtained among the linked units. We have performed a series of these experiments, using pairs of sticky ends that flank each of the six angles of a four‐arm junction. In every case, the ligated junctions are separated by 20 nucleotide pairs, about two turns of DNA. All expected short linear products, starting with dimers, are observed for all ligations. All ligations result in a macrocyclic series that begins with trimers. Thus, over the time scale of these reactions, the arms of this junction can form angles as low as 60°. The response of this junction to torsional stress has been tested in a companion experiment. A smaller version of this same four‐arm junction has been oligomerized so that successive junctions are separated by 16 nucleotide pairs, approximately 1.5 turns of DNA. If junctions were as rigid as linear duplex DNA, this system would not be expected to form macrocycles until the continuous chain approaches the Shore–Baldwin limit, ca. 160 base pairs. However, macrocyclic closure is observed in a regular ligation ladder, starting from tetramers. Model building suggests that the most likely explanation for the observed closure is that the junction adopts two different conformations, which bend the continuous strand toward opposite grooves. The junction structures formed by these ligations represent fluctuations from equilibrium structures.
Models for the solution state structure of the (6–4) photoproduct of thymidylyl‐(3′ → 5′)‐thymidine derived via a distance‐ and angle‐constrained conformation search procedure
Authors: Taylor John‐Stephen , Garrett Daniel S. , Wang Michael J.
Published: December 2004

The further spectroscopic analysis and molecular modeling of the recently reported (6–4) photoproduct of thymidylyl‐(3′ → 5′)‐thymidine is described. Three‐hundred megahertz equilibrium difference nuclear Overhauser effect (NOE) spectra were obtained for the four proton singlets of the molecule, two of which have uncovered previously unreported NOEs between the TpH3′ proton and the TpH6 and pT methyl protons. Torsion angle and interproton distance information was derived from coupling constants, difference NOE data, and molecular mechanics calculations. This information, along with softened van der Waals calculations and ring‐closure constraints, was used to constrain conformation searches utilizing the SYBYL molecular modeling program subroutine SEARCH. Sets of angles derived from the ring‐search procedure were then used to construct three structures whose geometries were optimized by the energy minimization subroutines MAXIMIN and SIMPLEX. One‐, two‐, and three‐state models composed of these three structures are proposed for the solution state structure of the (6–4) product. These models are energetically sound and are consistent with the nmr data. The three derived structures are also compared to B‐form TpT.
Solid‐state conformations of aminosuccinyl peptides: Crystal structure of tert‐butyloxycarbonyl‐L‐leucyl‐L‐aminosuccinyl‐L‐phenylalaninamide
Authors: Capasso S. , Mazzarella L. , Sica F. , Zagari A.
Published: December 2004

The protected tripeptide tert‐butyloxycarbonyl‐L‐leucyl‐L‐aminosuccinyl‐L‐phenylalaninamide crystallizes in the orthorhombic space group P212121, with a = 6.214(3), b = 12.832(3), c = 33.094(4) Å, Z = 4. The structure was solved by direct methods using MULTAN 80 and refined to an R value of 0.055 for 1458 reflections. The bond lengths and angles are in good agreement with the standard values. The peptide backbone adopts a type II′ β‐bend conformation with a weak intramolecular hydrogen bond between the CO group of the leucyl residue and the C‐terminal NH2 group. In agreement with previous studies, this structure confirms the high propensity of aminosuccinyl peptides to adopt a type II′ β‐bend conformation. The role of this conformation in relation to the deamidation process in proteins is also discussed.
Synthesis and structural studies of N‐p‐toluensulfonyl cyclodipeptides
Authors: Calcagni A. , Lucente G. , Mazza F. , Pochetti G. , Rossi D.
Published: December 2004

In view of the chemical and structural interest of cyclopeptides bearing an electron withdrawing substituent directly bonded at the amide nitrogen atom, the two N‐p‐toluensulfonyl (N‐tosyl) derivatives cyclo[‐Phe(Tos)‐D‐Phe‐] (I) and cyclo[‐Phe(Tos)‐D‐Pro‐] (II) have been synthesized and their stereochemistry defined. The molecular structure of I, as determined by x‐ray diffraction analysis, is reported together with 1H‐nmr parameters indicating the preferred rotameric conformation in chloroform solution. The N‐tosyl group alters the geometry of the cyclodipeptide ring by lengthening both the NC bonds departing from the tosylated nitrogen and reducing the corresponding ring angle. The 6‐membered peptide ring adopts an unusual “sofa” conformation with the Tos‐Phe Cα atom deviating 0.230(3) Å out of the mean plane of the other five ring atoms. One of the two SO bonds forms a planar system that involves the tosylated nitrogen and the corresponding amide carbonyl. In the crystal, both the benzylic side chains are folded over the heterocyclic ring, whereas in chloroform solution, the benzylic side chain of the D‐Phe prefers an extended conformation.
Design and conformation of non‐Aib synthetic peptides enjoying alamethicin‐like ionophore activity
Authors: Molle G. , Duclohier H. , Dugast J.‐Y. , Spach G.
Published: December 2004

Analogues of alamethicin, a 20‐mer amphipathic helical peptide with ionophore activity, in the sequence of which all Aib residues were substituted by Ala (A1) or Leu (L1), were synthesized by the solid phase method, purified by high performance liquid chromatography and characterized by fast atomic bombardment mass spectrometry. Infrared and CD studies showed that A1 easily underwent a transconformation to β‐structure whereas L1 displayed a predominant α‐helical character, thus being a potential ionophore model. Its voltage‐dependent multistate activity in model membrance showed that Aib is not a requisite residue to observe an alamethicin‐like behavior. However, as the lifetime of the single channels was much shorter than for alamethicin, the peptide chain was lengthened by a Leu (LL1) or a Ser (SL1) residue. The last peptide gave an increased channel lifetime, but the design of other non‐Aib peptides, taking into account the hydroxyl C‐terminus and side‐chain interactions between helices in a barrel‐stave bundle, is desirable to approach more closely the alamethicin activity.
Ala analogues of the cyclolinopeptide A
Authors: Zanotti Giancarlo , Tancredi Teodorico , Rossi Filomena , Benedetti Ettore , Pedone Carlo , Temussi Pierandrea
Published: December 2004

Analogues of cyclolinopeptide A, due to the replacement of each amino acid in the Pro1‐Pro2‐Phe3‐Phe4 sequences with an L‐Ala residue, were synthesized by classical method in solution. Mixed anhydride and N,N′‐dicyclohexylcarbodiimide coupling methods have been used for the synthesis of both linear and cyclic peptides. The products were characterized by Rf values and uv spectra, as well as by fast atom bombardment spectroscopy.

1H‐nmr studies on [Ala2] analogues are also reported. Preliminary data in CDCI3 solution, at low temperature, seems more promising.
Electron microscopy of native xanthan and xanthan exposed to low ionic strength
Authors: Stokke Bjørn T. , Smidsrød Olav , Elgsaeter Arnljot
Published: December 2004

Optical rotation data indicate that xanthan can exist both in an ordered and a disordered conformation. Using molecular weights obtained from light scattering measurements and contour length distributions obtained from electron micrographs, we find that a native, filtered xanthan exposed to low salinity (< 10−4M NaCl) and subsequently returned to 0.1M NaCl has a highly elongated structure with a mass per unit length of 1950 ± 200 Dalton/nm. Our data thus suggest that the ordered conformation of this xanthan is double stranded. We find that native, filtered xanthan in 0.1M NH4Ac has a nearly similar structure, but exists in part as aggregates of varying shape and size. Electron micrographs of these xanthans in 10−4M NH4Ac (the disordered conformation) display a mixture of species ranging from unaggregated single‐ or perfectly matched double‐stranded species, to double‐stranded chains branching into its two subunits as well as double‐stranded chains with different degrees of mismatching. This study suggests that the perfectly matched antiparallel or parallel double‐stranded chain constitutes the lowest free energy state of the ordered conformation of xanthan in dilute aqueous solution.
Relaxed potential energy surfaces of maltose
Authors: Tran Vinh , Buleon Alain , Imberty Anne , Perez Serge
Published: December 2004

Experimentally observed solution conformations of carbohydrate molecules might correspond to a dynamical average of several interconverting conformers in solution. In order to understand and describe more precisely molecular flexibility and motions, new computational routes have to be envisaged. Compared to conventional approaches where sugar residues are treated as rigid, the optimization of all the internal parameters—i.e., bond angles, valence angles, and all torsional angles—is an important step toward more realistic information. Here we report the calculations of potential energy surfaces where all the internal coordinates of the molecules were “relaxed” and minimized through an extensive molecular mechanics scheme. For this work, a prototypical carbohydrate system, the disaccharide α‐maltose, was selected. The inclusion of the relaxed principle into conformational description of maltose does not generally alter the overall shape of the allowed low‐energy regions, or the position of the local minima. However, flexibility within the ring plays a crucial role. Its principle effect is the lowering of energy barriers to conformational transitions about the glycosidic bonds, permitting pathways among the low‐energy minima. This occurs with retaining the overall 4C1 conformation of the glucose residues. The torsional angles corresponding to the orientations of the hydroxyl groups, especially the primary hydroxyl ones, display stable arrangements separated by energy barriers. They create subpopulations of stable conformers and it has not been possible to take into consideration interconversion of one subpopulation to another one. A “synthetic” relaxed potential energy surface is proposed, which can provide a realistic starting base for further investigation of solution behavior of dynamic simulations.
Association kinetics of site‐specific protein‐DNA interactions: Roles of nonspecific DNA sites and of the molecular location of the specific site
Authors: Mazur Sharlyn J. , Record M. Thomas
Published: December 2004

We have applied the formalism developed previously for the kinetics of domain‐localized reaction [S. Mazur and M. T. Record, Jr. (1986) Biopolymers 25, 985–1008] to describe complex mechanisms of association of a protein with a specific site on a large DNA molecule also containing many nonspecific binding sites. These nonspecific sites participate in the mechanism of formation of the specific complex through competitive binding and the facilitating mechanisms of sliding and transfer. The effects of localizing the sites in a domain are represented by a simple algebraic expression, and the sequence of interactions within the domain are described by equations closely related to a conventional, homogeneous solution mechanism. We apply this formalism to examine the interplay between sliding and direct transfer in domain‐localized interactions in general and in the lac repressor‐lac operator interaction in particular. Experimental investigation of the effect of the molecular location of the specific site (e.g., end vs middle of the polymer chain) on the kinetics of association may allow the contributions of sliding and direct transfer to be resolved.
Monte carlo studies on equilibrium globular protein folding. II. β‐barrel globular protein models
Authors: Skolnick Jeffrey , Kolinski Andrzej , Yaris Robert
Published: December 2004

In the context of dynamic Monte Carlo simulations on a model protein confined to a tetrahedral lattice, the interplay of protein size and tertiary structure, and the requirements for an all‐or‐none transition to a unique native state, are investigated. Small model proteins having a primary sequence consisting of a central bend neutral region flanked by two tails having an alternating hydrophobic/hydrophilic pattern of residues are seen to undergo a continuous transition to a β‐hairpin collapsed state. On increasing the length of the tails, the β‐hairpin structural motif is found to be in equilibrium with a four‐member β‐barrel. Further increase of the tail length results in the shift of the structural equilibrium to the four‐member β‐barrel. The random coil to β‐barrel transition is of an all‐or‐none character, but while the central turn is always the desired native bend, the location of the turns involving the two external strands is variable. That is, β‐barrels having the external stands that are two residues out of register are also observed in the transition region. Introduction into the primary sequence of two additional regions that are at the very least neutral toward turn formation produces an all‐or‐none transition to the unique, native, four‐member β‐barrel. Various factors that can augment the stability of the native conformation are explored. Overall, these folding simulations strongly indicate that the general rules of globular protein folding are rather robust—namely, one requires a general pattern of hydrophobic/hydrophilic residues that allow the protein to have a welldefined interior and exterior and the presence of regions in the amino acid sequence that at the very least are locally indifferent to turn formation. Since no site‐specific interactions between hydrophobic and hydrophilic residues are required to produce a unique four‐member β‐barrel, these simulations strongly suggest that site specificity is involved in structural fine‐tuning.
Monte carlo studies on equilibrium globular protein folding. III. The four helix bundle
Authors: Sikorski Andrzej , Skolnick Jeffrey
Published: December 2004

The nature of the equilibrium conformational transition from the denatured state to a four‐member α‐helical bundle was studied employing a dynamic Monte Carlo algorithm in which the model protein chain was confined to a tetrahedral lattice. The model chain was allowed to hunt over all phase space, the target native state was not assumed a priori, and no site‐specific interactions were introduced. The exterior vs the interior part of the protein is distinguished by the pattern of hydrophilic and hydrophobic interactions encoded into the primary sequence. The importance of a statistical preference for forming bends, as a function of bend location in the primary sequence, and helical wheel type cooperative interactions were examined, and the necessary conditions for collapse of the chain to the unique native structure were investigated. It was found that an amphipathic pattern of hydrophobic/hydrophilic interactions along with a statistical preference of the central residues for bend formation are sufficient to obtain the four‐helix bundle. The transition to the native state has an all‐or‐none character.
Solvation thermodynamics of biopolymers. I. Separation of the volume and surface interactions with estimates for proteins
Authors: Ben‐Naim A. , Ting K.‐L. , Jernigan R. L.
Published: December 2004

The present paper is a systematic first approach to the problem of solvation thermodynamics of biomolecules.

Most previous approaches have been only crude estimates of solvent contributions, and have simply assessed solvation free energy as proportional to surface areas.

Here we estimate the various contributions and divide them into (a) hard‐core interactions dependent upon the entire volume of solute and (b) the remainder of interactions manifested through surfaces, such as van der Waals, charge—charge, or hydrogen bonds. We have estimated the work to create a cavity with scaled‐particle theory (SPT), the van der Waals interactions on the surface, and hydrogen bonds between the surface and the solvent. The conclusion here is that this latter term is the largest component of the solvation free energy of proteins.

From estimates on nine diverse proteins, it is clear that the larger the protein, the more dominant is the hydrogen‐bond term. In the next paper, we indicate that correlations between hydrogen‐bonding groups on the surfaces could increase the magnitude of the hydrogen‐bond contribution.
The regulation of size and form in the assembly of collagen fibrils in vivo
Authors: Chapman John A.
Published: December 2004

A possible mechanism for regulating the lateral growth of collagen fibrils in vivo is considered. A growth inhibitor associated with a particular part of the long semiflexible collagen molecule restricts that part of the molecule to the surface of the growing assembly. Lateral accretion ceases when these inhibitors form a complete circumferential layer around the fibril surface. Cell‐mediated removal of the inhibitors allows lateral growth to proceed to a second limiting layer, and so on to subsequent limiting layers. In this way, cycles of inhibitor removal and limited lateral accretion permit growth to be synchronized over large populations of fibrils. Observed diameter distributions in bundles of embryonic and neonatal fibrils are those expected from a mechanism of this kind. The mechanism depends on the existence of axial order (D‐periodicity) in fibrils, but not on any specific lateral packing of molecules. Rather, contacts between newly assembled molecules are presumed to be partly fluid‐like in lateral directions (except where covalent cross‐links have formed). Some initial fluidity in lateral packing prior to cross‐linking does not preclude the subsequent emergence of quasi‐crystalline packing as cross‐links form. The cylindrical shape of fibrils in vivo may also be attributable in part to fluidity of intermolecular contacts at the growing surface.
Electric dichroism and bending amplitudes of DNA fragments according to a simple orientation function for weakly bent rods
Authors: Porschke Dietmar
Published: December 2004

The linear dichroism is calculated for DNA fragments in their thermal bending equilibrium. These calculations are given for relatively short fragments, where bent molecules can be described by an arc model. Using the measured value of 350 Å for the persistence length, the limit dichroism (corresponding to complete alignment) decreases due to thermal bending, e.g., for a fragment with 100 base pairs to 80% of the value expected for straight molecules. Thermal bending should lead to a strong continuous decrease of the dichroism with increasing chain length, which is not observed, however, in electric dichroism experiments due to electric stretching. The influence of the electric field on the bending equilibrium is described by a contribution to the bending energy, which is calculated from the movement of charge equivalents against the potential gradient upon bending. The charge equivalents, which are assigned to the helix ends, are derived from the dipole moments causing the stationary degree of orientation. By this procedure the energy term inducing DNA stretching is given for induced, permanent, and saturating induced dipole models without introduction of any additional parameter. The stationary dichroism at a given electric field strength is then calculated according to an arc model by integration over all angles of orientation of helix axes or chords with respect to the field vector, and at each of these angles the contribution to the dichroism is calculated by integration over all helices with different degrees of bending. Orientation functions obtained by this procedure are fitted to dichroism data measured for various restriction fragments. Optimal fits are found for an induced dipole model with saturation of the polarizability. The difference between orientation functions with and without electric stretching is used to evaluate dichroism bending amplitudes. Both chain length and field strength dependence of bending amplitudes are consistent with experimental amplitudes derived from the dichroism decay in low salt buffers containing multivalent ions like Mg2+, spermine, or [(CoNH3)6]3+. Bending amplitudes can be used to evaluate the persistence length from electrooptical data obtained for a single DNA restriction fragment. Bending and stretching effects are considerable already at relatively low chain length, and thus should not be neglected in any quantitative evaluation of experimental data.
Inverted repeat sequences can influence the melting transitions of linear DNAs
Authors: McCampbell Charles R. , Wartell Roger M. , Plaskon R. Richard
Published: December 2004

The influence of inverted repeat sequences on the melting transitions of linear of DNAs has been examined. Derivative melting curves (DMC) of a 514 base pair (bp) DNA, seven subfragments of this DNA, and four other DNAs have been compared to predictions of DNA melting theory. The 514‐bp DNA contains three inverted repeat sequences that can form cruciform structures in supercoiled DNA. We refer to these sequences as c‐inverted repeats. Previous work showed that the DMC of this DNA, unlike a number of other DNAs, is not accurately predicted by DNA melting theory. Since the theoretical model does not include hairpin‐like structures, it was suggested that hairpin or cruciform formation in these inverted repeats may be responsible for this discrepancy. Our results support this hypothesis. Predicted DMCs are in good agreement with DNAs with no inverted repeats, or inverted repeats not evident in supercoiled DNA. Differences between the theoretical and experimental Tm's are ≤ 0.3°C. DNA molecules that contain one or more of the three c‐inverted repeats are not as accurately predicted. Experimental Tm values are lower than predicted values by 0.7–3.8°C. It is concluded that some inverted repeat sequences can form hairpin‐like structures during the melting of linear DNAs. These structures appear to lower overall DNA stability.
The influence of the side‐chain sequence on the structure–activity correlations of immunomodulatory branched polypeptides. Synthesis and conformational analysis of new model polypeptides
Authors: Mező G. , Hudecz F. , Kajtár J. , Szókán Gy. , Szekerke M.
Published: December 2004

New branched polypeptides were synthesized for a detailed study of the influence of the side‐chain structure on the conformation and biological properties. The first subset of polypeptides were prepared by coupling of tetrapeptides to poly[L‐Lys]. These polymers contain either DL‐Ala3‐X {poly[Lys‐(X‐DL‐Ala3)n]} X‐DL‐Ala3 {poly[Lys‐(DL‐Ala3‐X)n] (n ≤ 1)} tetrapeptide side chains. Another group of branched polymers comprise a mixture of DL‐Alam and of DL‐Alam‐X oligomeric branches in a random distribution {poly[Lys‐(DL‐Alam‐Xi)](i < 1, m ∼ 3)}. In each subset the X = Leu or Phe derivatives were prepared.

The N‐protected tetrapeptides were synthesized by conventional liquid phase methods and were coupled as active esters. The degree of racemization was found relatively high both for active esters and coupled derivatives, when optically active amino acids were in the C‐terminal position of the tetrapeptides. In the case of the poly[Lys‐(Leu‐DL‐Ala3)n] derivative, comparative experiments were carred out using various methodical alterations. The highest stereochemical homogeniety could be achieved when the tetrapeptide active ester was synthesized by the “backing off” method.

CD spectra of poly[Lys‐(Xi‐DL‐Alam)] (i < 1, m ∼ 3) and of poly[Lys‐(X‐DL‐Ala3)n] were analyzed and compared to those of poly[Lys‐(DL‐Ala3‐Xi)] and of poly[Lys‐(DL‐Ala3‐X)n]. All measurements were performed in water solutions of varying pH values and ionic strengths. The data obtained suggest that branched polypeptides containing a mixture of two different types of oligomeric side chains (DL‐Alam and DL‐Alam‐Xi or Xi‐DL‐Alam) distributed randomly adopt an almost indentical conformation to those that comprise only the respective tetrapeptide (DL‐Ala3‐X or X‐DL‐Ala3) branches. The results also indicate that the tendency to form an ordered structure is determined by the indentity and the position of the chiral amino acid X (Phe or Leu) in the side chain.
Vibrational free energy, entropy, and temperature factors of DNA calculated by a helix lattice approach
Authors: Girirajan K. S. , Young L. , Prohofsky E. W.
Published: December 2004

The vibrational contribution to the free energy, entropy, and the temperature factors of the different atoms in the unit cell are calculated using the method of helix lattice dynamics for the DNA homopolymer poly(dG · poly(dC)) in the B conformation. These results are compared to other theoretical calculations and the temperature (B) factors are compared to experiment as well. The problems encountered in using small molecule approximations to describe B factors in DNA like long chain molecules are discussed and a corrected estimate of the temperature factors are presented. Significant differences are found between the different theoretical approaches as reflected in the results of temperature factor calculations.
I – V characteristics and electrical conductivity of synthetic melanin
Authors: Osak Władysław , Tkacz Katarzyna , Czternastek Halina , SłAwiński Janusz
Published: December 2004

I – V characteristics for synthetic melanin were investigated at – 10 and 25°C. It was found that the Ohm law is valid for low voltages whereas the Child law holds for higher ones. Furthermore, the steady state electrical conductivity was estimated. The change of activation energy from 0.76 eV for low temperatures to 1.58 eV was noticeable near 0°C.
Vibrational CD studies of the solution conformation of simple alanyl peptides as a function of pH
Authors: Zuk William M. , Freedman Teresa B. , Nafie Laurence A.
Published: December 2004

The CH‐stretching vibrational CD (VCD) spectra of glycyl‐L‐alanine, L‐alanylglycine, and L‐alanyl‐L‐alanine have been studied at neutral, high, and low pH in D2O solution. The intense positive VCD band attributed to the CαH stretch of the alanyl residue in glycyl‐L‐alanine at neutral pH is absent in L‐alanylglycine. In contrast to the VCD spectra of L‐alanine, the positive methine‐stretching VCD band in glycyl‐L‐alanine and L‐alanyl‐L‐alanine is still present at pH 2. Based on the ring current mechanism, the VCD spectra are consistent with the presence of a five‐membered CO … HN intramolecular hydrogen‐bonded ring between the C‐terminal carboxylate and peptide NH groups at neutral and high pH, and a seven‐membered COH … OC hydrogen‐bonded ring between the C‐terminal carboxyl OH and peptide CO groups at low pH. In the N‐terminal alanyl residue, the peptide CO group is hydrogen bonded to the NH trans to the methine bond. The CH‐stretching VCD spectra of L‐alanyl‐L‐alanyl‐L‐alanine at neutral pH are consistent with two intramolecularly hydrogen‐bonded conformations for the central alanyl residue.
Interactions of nucleic acids with distamycins. The drug monomeric chromophore
Authors: Forni A. , Moretti I. , Torre G. , Marconi G. , Samori B.
Published: December 2004

A study of the monomeric chromophore of the oligopeptides netropsin (1), distamycin III (2), and distamycin V (3) by polarization spectroscopy techniques1 and molecular orbital calculations is reported. Linear dichroism spectra of the monomeric model compounds 1‐methyl‐2(ethylcarbamoyl)‐4‐acetamido‐pyrrole (4) and 1‐methyl‐2(ethylcarbamoyl)‐pyrrole (5) dissolved and oriented in lyotropic and thermotropic liquid crystals provide, together with the magnetic CD spectra, experimental checks of the theoretical calculations. The polarization directions of the investigated transition obtained by these means in this study allow us to build up in the following paper2 the exciton states of (1)‐(3) and these provide a stereochemical interpretation of the flow linear dichroism spectra of the complexes of DNA with (2) and (3).
Side‐chain interactions in the C‐peptide helix: Phe 8 ⃛ His 12+
Authors: Shoemaker Kevin R. , Fairman Robert , Schultz David A. , Robertson Andrew D. , York Eunice J. , Stewart John M. , Baldwin Robert L.
Published: December 2004

Previous studies have demonstrated that His 12 plays a major role in the pH‐dependent stability of the helix formed by the isolated C‐peptide (residues 1–13 of ribonuclease A). Here, amino acid replacement experiments show that His 12+ stabilizes the C‐peptide helix chiefly by interacting with Phe 8. The Phe 8 ⃛ His 12+ ring interaction is specific for the protonated form of His 12 (His 12+) and the interaction is not screened significantly by NaCl, unlike the charged group ⃛ helix dipole interactions studied earlier in C‐peptide. Analogs of C‐peptide that are unable to form the Phe 8 ⃛ His 12+ interaction show large increases in helix content for Phe → Ala and His → Ala. Therefore, the helical tendencies of the individual residues Phe, His, and Ala are important in determining the result of a replacement experiment. Since the side chains of Phe 8 and His 12 probably interact within the N‐terminal helix of ribonuclease A, the existence of the Phe 8 ⃛ His 12+ interaction in the isolated C‐peptide helix adds to the evidence that the C‐peptide helix is an autonomous folding unit.
Synthesis of analogues of peptide YY with modified N‐terminal regions: Relationships of amphiphilic secondary structures and activity in rat vas deferens
Authors: Minakata Hiroyuki , Iwashita Takashi
Published: December 2004

Peptide YY (PYY) not only has distinct sequence homology with neuropeptide Y (NPY) and avian pancreatic polypeptide (APP), but it also exhibits both NPY‐ and APP‐like biological activities. We synthesized two analogues of PYY, A1 and A2, with modified N‐terminal regions, and compared their chemical and biological properties to those of PYY and the C‐terminal fragment of PYY, (13–36)PYY. This study shows that there is a good correlation between the stability of amphiphilic α‐helical structure and the biological activity of these peptides. A CD study of (13–36)PYY in mixed H2O and trifluoroethanol (TFE) solutions indicated a significant increase in α‐helical segments (26–79%) with increasing TFE proportions. Since the fragment (13–36)PYY had potent activity in the rat vas deferens (RVD) assay, the secondary structure is possibly required on the RVD cell surface receptors. The analogues, A1 and A2, were designed to increase the stability of the α‐helical structures by incorporation of modified N‐terminal regions. The CD studies, and the RVD assays of A1 and A2, suggest that the amphiphilic α‐helical structures are stabilized by intramolecular hydrophobic interactions with the N‐terminal regions and/or by intermolecular hydrophobic interactions in the self‐association process, and subsequently potentiate the activities of the peptides compared to those of PYY and (13–36)PYY.
Conformationally constrained α‐helical peptide models for protein ion channels
Authors: DeGrado W. F. , Lear J. D.
Published: December 2004

Recently we described the design, synthesis, and characterization of some simple amphiphilic α‐helical models for protein ion channels. These peptides, composed of only Leu and Ser residues, are hypothesized to form helical bundles capable of passing ions across phospholipid bilayers. In an effort to demonstrate that the peptides are, in fact, helical in their active ion‐conducting state, the conformationally constrained amino acid, Cα, Cα‐dimethylglycine (α‐aminoisobutyric acid, Aib), was introduced simulataneously at three positions into one of the model peptides, H2N‐(Leu‐Ser‐Leu‐Leu‐Leu‐Ser‐Leu)3‐CONH2, giving H2N‐(Leu‐Ser‐Leu‐Aib‐Leu‐Ser‐Leu)3‐CONH2. Examination of a tetrameric model for the channel suggested that this substitution should have a minimal effect on conductance. CD spectroscopy of the Aib‐modified and original peptide in phospholipid vesicles indicated that both were highly α‐helical. Furthermore, the Aib‐containing peptide formed proton channels nearly identical in conductance to the original peptide.