pinecone/core-2020-05-10-deduplication huggingface dataset:
QMX: A versatile environment for hybrid calculations applied to the grafting of Al2Cl3Me3 on a silica surface

International audienceWe present a new software to easily perform QM:MM and QM:QM' calculations called QMX. It follows the subtraction scheme and it is implemented in the Atomic Simulation Environment (ASE). Special attention is paid to couple molecular calculations with periodic boundaries approaches. QMX inherits the flexibility and versatility of the ASE package: any combination of methods namely force field, semiempirical, first principle, and ab initio, can be used as hybrid potential energy surface (PES). Its ease of use is demonstrated by considering the adsorption of Al2Cl3Me3 on silica surface and by combining different levels of theory (from standard DFT to MP2 calculations) for the so-called High Level cluster with standard PW91 density functional theory calculations for the Low Level environment. It is shown that the High Level cluster must contain the silanol group close to the aluminum atoms. The bridging adsorption is favored by 58 kJ mol−1 at the MP2:PW91 level with respect to the terminal position. Using large clusters at the MP2:PW91 level, it is shown that PW91 calculations are sufficient for structure optimization but that embedded methods are required for accurate energy profiles. © 2013 Wiley Periodicals, Inc
Toward quantitative estimates of binding affinities for protein-ligand systems involving large inhibitor compounds: A steered molecular dynamics simulation route

Understanding binding mechanisms between enzymes and potential inhibitors and quantifying protein–ligand affinities in terms of binding free energy is of primary importance in drug design studies. In this respect, several approaches based on molecular dynamics simulations, often combined with docking techniques, have been exploited to investigate the physicochemical properties of complexes of pharmaceutical interest. Even if the geometric properties of a modeled protein–ligand complex can be well predicted by computational methods, it is still challenging to rank with chemical accuracy a series of ligand analogues in a consistent way. In this article, we face this issue calculating relative binding free energies of a focal adhesion kinase, an important target for the development of anticancer drugs, with pyrrolopyrimidine-based ligands having different inhibitory power. To this aim, we employ steered molecular dynamics simulations combined with nonequilibrium work theorems for free energy calculations. This technique proves very powerful when a series of ligand analogues is considered, allowing one to tackle estimation of protein–ligand relative binding free energies in a reasonable time. In our cases, the calculated binding affinities are comparable with those recovered from experiments by exploiting the Michaelis–Menten mechanism with a competitive inhibitor.Peer ReviewedPostprint (published version
Highly asymmetric electrolytes in the primitive model: Hypernetted chain
  solution in arbitrary spatial dimensions

The pair-correlation functions for fluid ionic mixtures in arbitrary spatial
dimensions are computed in hypernetted chain (HNC) approximation. In the
primitive model, all ions are approximated as non-overlapping hyperspheres with
Coulomb interactions. Our spectral HNC solver is based on a Fourier-Bessel
transform introduced by Talman [J. Comput. Phys., 29, 35 (1978)], with
logarithmically spaced computational grids. Numeric efficiency for arbitrary
spatial dimensions is a commonly exploited virtue of this transform method.
Here, we highlight another advantage of logarithmic grids, consisting in
efficient sampling of pair-correlation functions for highly asymmetric ionic
mixtures. For three-dimensional fluids, ion size- and charge-ratios larger than
one thousand can be treated, corresponding to hitherto computationally not
accessed micrometer-sized colloidal spheres in 1-1 electrolyte. Effective
colloidal charge numbers are extracted from our primitive model results. For
moderately large ion size- and charge-asymmetries, we present Molecular
Dynamics simulation results that agree well with the approximate HNC pair
correlations
LEAP: highly accurate prediction of protein loop conformations by integrating coarse-grained sampling and optimized energy scores with all-atom refinement of backbone and side chains

Prediction of protein loop conformations without any prior knowledge (ab initio prediction) is an unsolved problem. Its solution will significantly impact protein homology and template-based modeling as well as ab initio protein-structure prediction. Here, we developed a coarse-grained, optimized scoring function for initial sampling and ranking of loop decoys. The resulting decoys are then further optimized in backbone and side-chain conformations and ranked by all-atom energy scoring functions. The final integrated technique called loop prediction by energy-assisted protocol achieved a median value of 2.1 Å root mean square deviation (RMSD) for 325 12-residue test loops and 2.0 Å RMSD for 45 12-residue loops from critical assessment of structure-prediction techniques (CASP) 10 target proteins with native core structures (backbone and side chains). If all side-chain conformations in protein cores were predicted in the absence of the target loop, loop-prediction accuracy only reduces slightly (0.2 Å difference in RMSD for 12-residue loops in the CASP target proteins). The accuracy obtained is about 1 Å RMSD or more improvement over other methods we tested. The executable file for a Linux system is freely available for academic users at http://sparks-lab.org
Rapid determination of RMSDs corresponding to macromolecular rigid body motions

International audienceFinding the root mean sum of squared deviations (RMSDs) between two coordinate vectors that correspond to the rigid body motion of a macromolecule is an important problem in structural bioinformatics, computational chemistry, and molecular modeling. Standard algorithms compute the RMSD with time proportional to the number of atoms in the molecule. Here, we present RigidRMSD, a new algorithm that determines a set of RMSDs corresponding to a set of rigid body motions of a macromolecule in constant time with respect to the number of atoms in the molecule. Our algorithm is particularly useful for rigid body modeling applications, such as rigid body docking, and also for high-throughput analysis of rigid body modeling and simulation results. We also introduce a constant-time rotation RMSD as a similarity measure for rigid molecules. A C++ implementation of our algorithm is available at http://nano-d.inrialpes.fr/software/RigidRMSD
Carbohydrate-binding protein identification by coupling structural similarity searching with binding affinity prediction

Carbohydrate-binding proteins (CBPs) are potential biomarkers and drug targets. However, the interactions between carbohydrates and proteins are challenging to study experimentally and computationally because of their low binding affinity, high flexibility, and the lack of a linear sequence in carbohydrates as exists in RNA, DNA, and proteins. Here, we describe a structure-based function-prediction technique called SPOT-Struc that identifies carbohydrate-recognizing proteins and their binding amino acid residues by structural alignment program SPalign and binding affinity scoring according to a knowledge-based statistical potential based on the distance-scaled finite-ideal gas reference state (DFIRE). The leave-one-out cross-validation of the method on 113 carbohydrate-binding domains and 3442 noncarbohydrate binding proteins yields a Matthews correlation coefficient of 0.56 for SPalign alone and 0.63 for SPOT-Struc (SPalign?+?binding affinity scoring) for CBP prediction. SPOT-Struc is a technique with high positive predictive value (79% correct predictions in all positive CBP predictions) with a reasonable sensitivity (52% positive predictions in all CBPs). The sensitivity of the method was changed slightly when applied to 31 APO (unbound) structures found in the protein databank (14/31 for APO versus 15/31 for HOLO). The result of SPOT-Struc will not change significantly if highly homologous templates were used. SPOT-Struc predicted 19 out of 2076 structural genome targets as CBPs. In particular, one uncharacterized protein in Bacillus subtilis (1oq1A) was matched to galectin-9 from Mus musculus. Thus, SPOT-Struc is useful for uncovering novel carbohydrate-binding proteins. SPOT-Struc is available at http://sparks-lab.org.Full Tex
The adaptive buffered force QM/MM method in the CP2K and AMBER software packages

The implementation and validation of the adaptive buffered force (AdBF) quantum-mechanics/molecular-mechanics (QM/MM) method in two popular packages, CP2K and AMBER are presented. The implementations build on the existing QM/MM functionality in each code, extending it to allow for redefinition of the QM and MM regions during the simulation and reducing QM-MM interface errors by discarding forces near the boundary according to the buffered force-mixing approach. New adaptive thermostats, needed by force-mixing methods, are also implemented. Different variants of the method are benchmarked by simulating the structure of bulk water, water autoprotolysis in the presence of zinc and dimethyl-phosphate hydrolysis using various semiempirical Hamiltonians and density functional theory as the QM model. It is shown that with suitable parameters, based on force convergence tests, the AdBF QM/MM scheme can provide an accurate approximation of the structure in the dynamical QM region matching the corresponding fully QM simulations, as well as reproducing the correct energetics in all cases. Adaptive unbuffered force-mixing and adaptive conventional QM/MM methods also provide reasonable results for some systems, but are more likely to suffer from instabilities and inaccuracies.N.B. acknowledges funding for this work by the Office of Naval Research through the Naval Research Laboratory's basic research program, and computer time at the AFRL DoD Supercomputing Resource Center through the DoD High Performance Computing Modernization Program (subproject NRLDC04253428). B.L. was supported by EPSRC (grant no. EP/G036136/1) and the Scottish Funding Council. G.C. and B.L. acknowledge support form EPSRC under grant no. EP/J01298X/1. R.C.W. and A.W.G. acknowledge financial support by the National Institutes of Health (R01 GM100934), A.W.G. acknowledges financial support by the Department of Energy (DE-AC36-99GO-10337). This work was partially supported by National Science Foundation (grant no. OCI-1148358) and used the Extreme Science and Engineering Discovery Environment (XSEDE), which is supported by National Science Foundation grant no. ACI-1053575. Computer time was provided by the San Diego Supercomputer Center through XSEDE award TG-CHE130010.This is the author accepted version of the article. The final published version is available from Wiley at http://onlinelibrary.wiley.com/doi/10.1002/jcc.23839/full
Estimating π binding energy of N-Heterocyclic carbenes: The role of polarization

International audienceIn this work, the tuneability of the π acceptor or donor properties of a set of N-heterocyclic carbenes (NHCs) with a wide spectrum of electronic characteristics is established by means of density functional theory and energy decomposition analysis (EDA) tools. Even though the main orbital interaction contribution to the NHC coordination is the σ donation, a significant contribution of the π interactions to the bond is observed. By means of carefully selected coordination sites, different contributions to the π interactions could be identified and isolated. It includes not only the well known back donation and donation interactions, but also the intrafragment polarization, which has not been considered in previous studies. This can be obtained through the use of the extended transition state method for EDA combined with the natural orbitals for chemical valence and the constrained space orbital variation analysis. The contributions vary with the position of the heteroatoms and the presence of exocyclic substituents; the donation/backdonation π interactions between NHC and the coordination site can range between 2 and 61% of the total π orbital interactions, while the rest is owed to intrafragment polarization. Our results do not only contribute to the understanding of the electronic structure of NHC-based complexes, giving ways to improve their catalytic properties, but also provide comprehension on the modelization methods used to study their donor–acceptor interactions
New ways to boost molecular dynamics simulations

Contains fulltext :
                  153502.pdf (publisher's version ) (Open Access)We describe a set of algorithms that allow to simulate dihydrofolate reductase (DHFR, a common benchmark) with the AMBER all-atom force field at 160 nanoseconds/day on a single Intel Core i7 5960X CPU (no graphics processing unit (GPU), 23,786 atoms, particle mesh Ewald (PME), 8.0 A cutoff, correct atom masses, reproducible trajectory, CPU with 3.6 GHz, no turbo boost, 8 AVX registers). The new features include a mixed multiple time-step algorithm (reaching 5 fs), a tuned version of LINCS to constrain bond angles, the fusion of pair list creation and force calculation, pressure coupling with a "densostat," and exploitation of new CPU instruction sets like AVX2. The impact of Intel's new transactional memory, atomic instructions, and sloppy pair lists is also analyzed. The algorithms map well to GPUs and can automatically handle most Protein Data Bank (PDB) files including ligands. An implementation is available as part of the YASARA molecular modeling and simulation program from www.YASARA.org
Efficient parametrization of complex molecule-surface force fields

We present an efficient scheme for parametrizing complex molecule-surface force fields from ab initio data. The cost of producing a sufficient fitting library is mitigated using a 2D periodic embedded slab model made possible by the quantum mechanics/molecular mechanics scheme in CP2K. These results were then used in conjunction with genetic algorithm (GA) methods to optimize the large parameter sets needed to describe such systems. The derived potentials are able to well reproduce adsorption geometries and adsorption energies calculated using density functional theory. Finally, we discuss the challenges in creating a sufficient fitting library, determining whether or not the GA optimization has completed, and the transferability of such force fields to similar molecules. Â© 2015 Wiley Periodicals, Inc
Inter- and intramolecular CF···C=O interactions on aliphatic and cyclohexane carbonyl derivatives

The authors thank EaStCHEM and the University of St Andrews for access to a computing facility managed by Dr H. Fruchtl., CNPq, and FAPESP for the studentship (to R.A.C. #2011/01170-1, FAPESP) and for financial support (#2014/25903-6), as well as CNPq for the fellowship (R.R.).The assessment of weak inter- and intra- molecular Cδ+Fδ-...Cδ+=Oδ- interactions were theoretically evaluated in 4 different sets of compounds at different theoretical levels. Intermolecular CH3F...C=O interactions were stabilizing by ca. 1 kcal mol-1 for various carbonyl containing functional groups. Intramolecular CF...C=O interactions were also detected in aliphatic and fluorinated cyclohexane carbonyl derivatives. However, the stabilisation provided by intramolecular CF...C=O interactions was not enough to govern the conformational preferences of compounds 2-4.PostprintPeer reviewe
QM/MM modeling of the hydroxylation of the androstenedione substrate catalyzed by cytochrome P450 aromatase (CYP19A1)

CYP19A1 aromatase is a member of the Cytochrome P450 family of hemeproteins, and is the enzyme responsible for the final step of the androgens conversion into the corresponding estrogens, via a three-step oxidative process. For this reason, the inhibition of this enzyme plays an important role in the treatment of hormone-dependent breast cancer. The first catalytic subcycle, corresponding to the hydroxilation of androstenedione, has been proposed to occur through a first hydrogen abstraction and a subsequent oxygen rebound step. In present work, we have studied the mechanism of the first catalytic subcycle by means of hybrid quantum mechanics/molecular mechanics methods. The inclusion of the protein flexibility has been achieved by means of Free Energy Perturbation techniques, giving rise to a free energy of activation for the hydrogen abstraction step of 13.5 kcal/mol. The subsequent oxygen rebound step, characterized by a small free energy barrier (1.5 kcal/mol), leads to the hydroxylated products through a highly exergonic reaction. In addition, an analysis of the primary deuterium kinetic isotopic effects, calculated for the hydrogen abstraction step, reveals values (∼10) overpassing the semiclassical limit for the C[BOND]H, indicating the presence of a substantial tunnel effect. Finally, a decomposition analysis of the interaction energy for the substrate and cofactor in the active site is also discussed. According to our results, the role of the enzymatic environment consists of a transition state stabilization by means of dispersive and polarization effects.We acknowledge the Servei d'Informàtica of the Universitat Jaume I, GENCI-CINES, and BSC-Marenostrum for providing us with computer capabilities. The authors thank V. Moliner for valuable comments and discussion
Best bang for your buck: GPU nodes for GROMACS biomolecular simulations

The molecular dynamics simulation package GROMACS runs efficiently on a wide
variety of hardware from commodity workstations to high performance computing
clusters. Hardware features are well exploited with a combination of SIMD,
multi-threading, and MPI-based SPMD/MPMD parallelism, while GPUs can be used as
accelerators to compute interactions offloaded from the CPU. Here we evaluate
which hardware produces trajectories with GROMACS 4.6 or 5.0 in the most
economical way. We have assembled and benchmarked compute nodes with various
CPU/GPU combinations to identify optimal compositions in terms of raw
trajectory production rate, performance-to-price ratio, energy efficiency, and
several other criteria. Though hardware prices are naturally subject to trends
and fluctuations, general tendencies are clearly visible. Adding any type of
GPU significantly boosts a node's simulation performance. For inexpensive
consumer-class GPUs this improvement equally reflects in the
performance-to-price ratio. Although memory issues in consumer-class GPUs could
pass unnoticed since these cards do not support ECC memory, unreliable GPUs can
be sorted out with memory checking tools. Apart from the obvious determinants
for cost-efficiency like hardware expenses and raw performance, the energy
consumption of a node is a major cost factor. Over the typical hardware
lifetime until replacement of a few years, the costs for electrical power and
cooling can become larger than the costs of the hardware itself. Taking that
into account, nodes with a well-balanced ratio of CPU and consumer-class GPU
resources produce the maximum amount of GROMACS trajectory over their lifetime
Attracting cavities for docking. Replacing the rough energy landscape of the protein by a smooth attracting landscape.

Molecular docking is a computational approach for predicting the most probable position of ligands in the binding sites of macromolecules and constitutes the cornerstone of structure-based computer-aided drug design. Here, we present a new algorithm called Attracting Cavities that allows molecular docking to be performed by simple energy minimizations only. The approach consists in transiently replacing the rough potential energy hypersurface of the protein by a smooth attracting potential driving the ligands into protein cavities. The actual protein energy landscape is reintroduced in a second step to refine the ligand position. The scoring function of Attracting Cavities is based on the CHARMM force field and the FACTS solvation model. The approach was tested on the 85 experimental ligand-protein structures included in the Astex diverse set and achieved a success rate of 80% in reproducing the experimental binding mode starting from a completely randomized ligand conformer. The algorithm thus compares favorably with current state-of-the-art docking programs
Scalable improvement of SPME multipolar electrostatics in anisotropic polarizable molecular mechanics using a general short-range penetration correction up to quadrupoles

International audienceWe propose a general coupling of the Smooth Particle Mesh Ewald (SPME) approach for distributed multipoles to a short-range charge penetration correction modifying the charge-charge, charge-dipole and charge-quadrupole energies. Such an approach significantly improves electrostatics when compared to ab initio values and has been calibrated on Symmetry-Adapted Perturbation Theory (SAPT) reference data. Various neutral molecular dimers have been tested as results on charged systems (metal cation complexes) are provided. Transferability of the correction is adressed in the context of the implementation of the AMOEBA and SIBFA polarizable force fields in the Tinker-HP software. As the choices of the multipolar distribution are discussed, Conclusions are drawn for the future penetration-corrected polarizable force fields highlighting the mandatory need of non-spurious procedures for the obtention of well balanced and physically meaningful distributed moments. Finally scalability and parallelism of the short-range corrected SPME approach are addressed, demonstrating that the damping function is computationally affordable and accurate for molecular dynamics simulationsof complexe bio- or bioinorganic systems in periodic boundary conditions
Competition between hydrogen and halogen bonding in halogenated 1-methyluracil: water systems

The competition between hydrogen- and halogen-bonding interactions in complexes of 5-halogenated 1-methyluracil (XmU; X = F, Cl, Br, I or At) with one or two water molecules in the binding region between C5-X and C4=O4 is investigated with M06-2X/6-31+G(d). In the singly-hydrated systems, the water molecule forms a hydrogen bond with C4=O4 for all halogens, whereas structures with a halogen bond between the water oxygen and C5-X exist only for X = Br, I and At. Structures with two waters forming a bridge between C4=O and C5-X (through hydrogen- and halogen-bonding interactions) exist for all halogens except F. The absence of a halogen-bonded structure in singly-hydrated ClmU is therefore attributed to the competing hydrogen-bonding interaction with C4=O4. The halogen-bond angle in the doubly-hydrated structures (150-160°) is far from the expected linearity of halogen bonds, indicating that significantly non-linear halogen bonds may exist in complex environments with competing interactions.PostprintPeer reviewe
Real-time feedback from iterative electronic structure calculations

Real-time feedback from iterative electronic structure calculations requires
to mediate between the inherently unpredictable execution times of the
iterative algorithm employed and the necessity to provide data in fixed and
short time intervals for real-time rendering. We introduce the concept of a
mediator as a component able to deal with infrequent and unpredictable
reference data to generate reliable feedback. In the context of real-time
quantum chemistry, the mediator takes the form of a surrogate potential that
has the same local shape as the first-principles potential and can be evaluated
efficiently to deliver atomic forces as real-time feedback. The surrogate
potential is updated continuously by electronic structure calculations and
guarantees to provide a reliable response to the operator for any molecular
structure. To demonstrate the application of iterative electronic structure
methods in real-time reactivity exploration, we implement self-consistent
semi-empirical methods as the data source and apply the surrogate-potential
mediator to deliver reliable real-time feedback.Comment: 9 pages, 10 figures, 2 table