Nonuniform charge scaling (NUCS): A practical approximation of solvent electrostatic screening in proteins
In molecular mechanics calculations, electrostatic interactions between chemical groups are usually represented by a Coulomb potential between the partial atomic charges of the groups. In aqueous solution these interactions are modified by the polarizable solvent. Although the electrostatic effects of the polarized solvent on the protein are well described by the Poisson--Boltzmann equation, its numerical solution is computationally expensive for large molecules such as proteins. The procedure of nonuniform charge scaling (NUCS) is a pragmatic approach to implicit solvation that approximates the solvent screening effect by individually scaling the partial charges on the explicit atoms of the macromolecule so as to reproduce electrostatic interaction energies obtained from an initial Poisson--Boltzmann analysis. Once the screening factors have been determined for a protein the scaled charges can be easily used in any molecular mechanics program that implements a Coulomb term. The approach is particularly suitable for minimization-based simulations, such as normal mode analysis, certain conformational reaction path or ligand binding techniques for which bulk solvent cannot be included explicitly, and for combined quantum mechanical/molecular mechanical calculations when the interface to more elaborate continuum solvent models is lacking. The method is illustrated using reaction path calculations of the Tyr 35 ring flip in the bovine pancreatic trypsin inhibitor.

title: How well does charge reparametrisation account for solvent screening in molecular mechanics calculations? The example of myosin
abstract: The rate constant of an enzyme-catalysed reaction is one of the major target properties to understand protein function. Atomic-detail computer simulations can in principle be used to estimate rate constants from the energy profile along the reaction coordinate. For such simulations, molecular mechanics is combined with a quantum description of the reaction process. In molecular mechanics calculations, the electrostatic field is represented by the Coulomb potential of partial atomic charges which have been parametrised for small building blocks in vacuum and transferred to the macromolecule. In aqueous solution, however, the electrostatic interactions are affected by the solvent polarization. While this can be described by numerically solving the Poisson-Boltzmann equation, it is computationally expensive. A simple approximation to this is to optimally reproduce the electrostatic potential in solution by reparametrising the partial atomic charges in such a way that a simple Coulomb potential can still be used. Such a procedure would allow to perform fast calculations of reaction processes in proteins while accounting for the solvent screening effect. Here, this method is tested on myosin, a motor protein that is both an enzyme and exists in very different conformations.

title: Docking by Monte Carlo minimization with a solvation correction: Application to an FKBP - substrate complex
abstract: A Monte Carlo docking procedure that combines random displacements of the substrate and protein side chains with minimization of the enzyme]substrate complex is described and applied to finding the binding mode of the blocked tetrapeptide N-acetyl-Leu-Pro-Phe-methylamide to the FK506 binding protein Ž .  The tetrapeptide, an analog of the preferred FKBP substrate, and the FKBP binding site are flexible during the docking procedure. The twisted-imide transition-state form of the substrate is used during docking. The enzyme charges are scaled individually to account for solvent screening of specific binding site residues during the Monte Carlo sampling. To evaluate the relative binding free energies of the resulting structures, a rapid method for calculating polar and nonpolar solvation effects is introduced. Accurate electrostatic solute]solvent energies are calculated by solving the finite-difference linearized Poisson]Boltzmann equation; nonpolar contributions to the stability of the different conformers are estimated by the free energy of cavity formation, which is obtained from the molecular surface, and the solute]solvent van der Waals energy, which is calculated with a continuum approach. In the conformation of the enzyme]substrate complex with the lowest free energy, the tetrapeptide is bound as a type VIa proline turn with solvent accessible ends to permit longer polypeptide chains to act as substrates. Except for the imide carbonyl, which is involved in polar interactions with aromatic side chains of the FKBP binding *Present address: Pharmaceutical Research, F. Hoffmann]La Roche Ltd., CH-4070 Basel, Switzerland. Author to whom all correspondence should be addressed. ( 21 CAFLISCH, FISCHER, AND KARPLUS site, all of the seven potential hydrogen bond donors or acceptors of the tetrapeptide are satisfied. The FKBP binding site has a similar conformation in the substrate complex as in the FKBP-FK506 cocrystal structure, except for the predicted reorientation of the Tyr 82 hydroxyl, which plays an important role in substrate binding. The present model for the FKBP]substrate complex is in agreement with the recently determined crystal structure of a cyclic peptide]FK506 hybrid bound to FKBP and supports the structure obtained previously by iterative model building. In addition, it is consistent with the observed effects of FKBP point mutations on the enzyme activity. The approach described here should be useful, in general, for the prediction of the structure of a molecule in solution or as part of a complex. It provides for the effective sampling of conformational space and for the inclusion of solvent effects. Q 1997 by John Wiley & Sons, Inc.

title: Can the calculation of ligand binding free energies be improved with continuum solvent electrostatics and an ideal-gas entropy correction?
abstract: The prediction of a ligand binding constant requires generating three-dimensional structures of the complex concerned and reliably scoring these structures. Here, the scoring problem is investigated by examining benzamidine-like inhibitors of trypsin, a system for which errors in the structures are small. Precise and consistent binding free energies for the inhibitors are determined experimentally for this test system. To examine possible improvement of scoring methods, we test the suitability of continuum electrostatics to account for solvation effects and use an ideal-gas entropy correction to account for the changes in the degrees of freedom of the ligand. The small observed root-mean-square deviation of 0.55 kcal/mol of the calculated relative to the experimental values indicates that the essentials of the binding process have been captured. Even though all six ligands make the same salt bridge and H-bonds to the protein, the electrostatic contribution varies among the ligands by as much as 2 kcal/mol. Moreover, although the ligands are rigid and similar in size, the entropic terms also significantly affect the relative binding affinities (by up to 2.7 kcal/mol). The present approach to solvation and entropy may allow the ranking of the ligands to be considerably improved at a cost that makes the method applicable to the optimization of lead compounds or to the screening of small collections of ligands.

title: Experiences with an Emotional Sales Agent
abstract: With COSIMAB2B we demonstrate a prototype of a complex and visionary e-procurement application. The embodied character agent named COSIMA is able to respect a customer’s preferences and deals with him or her via natural speech. She expresses various emotions via mimic, gesture, combined with speech synthesis, and COSIMA is even able to consider the customer’s emotions via mimic recognition. As first observations show, this is a very promising approach to improve the bargaining with the customer or the recommendation of products.

title: Evaluation and optimization of the catalog search process of e-procurement platforms
abstract: With the emerging of e-catalog standards the product search can be used in a very different and improved matter. Beyond the usual keyword search this opens the arena for attribute-based search engines, including parametric search and preference search. We analyze the impact of different search techniques for such e-catalogs on the overall search process costs. It turns out that preference search has a high potential to significantly reduce the process costs. A large-scale use case with the MAN2B e-procurement platform supports our claim. We identify improvements achievable by using preference search, in particular less navigation steps during the product search and better search results due to the BMO query model. Expensive cases, where frustrated users accept bad search results or phone up the company's purchasing department, should decrease significantly. This in turn will enable the purchasing department to focus more on strategic issues like supplier relationship management than on operative issues as it still happens widely today.

title: Graph Edit Distance with Node Splitting and Merging, and Its Application to Diatom Idenfication
abstract: A new graph matching scheme based on an extended set of edit operations, which include the splitting and merging of nodes, is proposed in this paper. This scheme is useful in applications where the nodes of the considered graphs represent regions extracted by some segmentation procedure from an image. To demonstrate the feasibility of the proposed method, its application to the automatic identification of diatoms (unicellular algae) is described.

title: Algebraic Immunity of S-Boxes and Augmented Functions
abstract: In this paper, the algebraic immunity of S-boxes and augmented functions of stream ciphers is investigated. Augmented functions are shown to have some algebraic properties that are not covered by previous measures of immunity. As a result, efficient algebraic attacks with very low data complexity on certain filter generators become possible. In a similar line, the algebraic immunity of the augmented function of the eSTREAM candidate Trivium is experimentally tested. These tests suggest that Trivium has some immunity against algebraic attacks on augmented functions.

title: Optimizing the catalog search process for e-procurement platforms
abstract: Many e-procurement platforms support XML-based e-catalogs combined with standardized feature descriptions. Beyond the usual keyword search this opens the arena for attribute-based search engines, including parametric search and preference search. We analyze the impact of different search techniques for such e-catalogs on the overall search process costs. It turns out that preference search has a high potential to significantly reduce the process costs. A large-scale use case with the MAN2B e-procurement platform supports our claim. We identify improvements achievable by using preference search, in particular less navigation steps during the product search and better search results due to the BMO query model. Expensive cases, where frustrated users accept bad search results or phone up the company's purchasing department, should decrease significantly. This in turn will enable the purchasing department to focus more on strategic issues like supplier relationship management than on operative issues as it still happens widely today.