Systematic improvement of empirical energy functions in the era of machine learning.

The impact of targeted replacement of individual terms in empirical force fields is quantitatively assessed for pure water, dichloromethane (CH 2 Cl 2 ), and solvated K + and Cl - ions. For the electrostatic interactions, point charges (PCs) and machine learning (ML)-based minimally distributed charges (MDCM) fitted to the molecular electrostatic potential are evaluated together with electrostatics based on the Coulomb integral. The impact of explicitly including second-order terms is investigated by adding a fragment molecular orbital (FMO)-derived polarization energy to an existing force field, in this case CHARMM. It is demonstrated that anisotropic electrostatics reduce the RMSE for water (by 1.4 kcal/mol), CH 2 Cl 2 (by 0.8 kcal/mol) and for solvated Cl - clusters (by 0.4 kcal/mol). An additional polarization term can be neglected for CH 2 Cl 2 but further improves the models for pure water (by ∼ 1.0 kcal/mol) and hydrated Cl - (by 0.4 kcal/mol), and is key for solvated K + , reducing the RMSE by 2.3 kcal/mol. A 12-6 Lennard-Jones functional form performs satisfactorily with PC and MDCM electrostatics, but is not appropriate for descriptions that account for the electrostatic penetration energy. The importance of many-body contributions is assessed by comparing a strictly 2-body approach with self-consistent reference data. Two-body interactions suffice for CH 2 Cl 2 whereas water and solvated K + and Cl - ions require explicit many-body corrections. Finally, a many-body-corrected dimer potential energy surface exceeds the accuracy attained using a conventional empirical force field, potentially reaching that of an FMO calculation. The present work systematically quantifies which terms improve the performance of an existing force field and what reference data to use for parametrizing these terms in a tractable fashion for ML fitting of pure and heterogeneous systems.

Host Dynamics under General-Purpose Force Fields.

Macrocyclic hosts as prototypical receptors to gaseous and drug-like guests are crucial components in pharmaceutical research. The external guests are often coordinated at the center of these macromolecular containers. The formation of host-guest coordination is accompanied by the broken of host-water and host-ion interactions and sometimes also involves some conformational rearrangements of the host. A balanced description of various components of interacting terms is indispensable. However, up to now, the modeling community still lacks a general yet detailed understanding of commonly employed general-purpose force fields and the host dynamics produced by these popular selections. To fill this critical gap, in this paper, we profile the energetics and dynamics of four types of popular macrocycles, including cucurbiturils, pillararenes, cyclodextrins, and octa acids. The presented investigations of force field definitions, refitting, and evaluations are unprecedently detailed. Based on the valuable observations and insightful explanations, we finally summarize some general guidelines on force field parametrization and selection in host-guest modeling.

Combining EXAFS and Computer Simulations to Refine the Structural Description of Actinyls in Water.

EXAFS spectroscopy is one of the most used techniques to solve the structure of actinoid solutions. In this work a systematic analysis of the EXAFS spectra of four actinyl cations, [UO2]2+, [NpO2]2+, [NpO2]+ and [PuO2]2+ has been carried out by comparing experimental results with theoretical spectra. These were obtained by averaging individual contributions from snapshots taken from classical Molecular Dynamics simulations which employed a recently developed [AnO2]2+/+ -H2O force field based on the hydrated ion model using a quantum-mechanical (B3LYP) potential energy surface. Analysis of the complex EXAFS signal shows that both An-Oyl and An-OW single scattering paths as well as multiple scattering ones involving [AnO2]+/2+ molecular cation and first-shell water molecules are mixed up all together to produce a very complex signal. Simulated EXAFS from the B3LYP force field are in reasonable agreement for some of the cases studied, although the k= 6-8 Å-1 region is hard to be reproduced theoretically. Except uranyl, all studied actinyls are open-shell electron configurations, therefore it has been investigated how simulated EXAFS spectra are affected by minute changes of An-O bond distances produced by the inclusion of static and dynamic electron correlation in the quantum mechanical calculations. A [NpO2]+-H2O force field based on a NEVPT2 potential energy surface has been developed. The small structural changes incorporated by the electron correlation on the actinyl aqua ion geometry, typically smaller than 0.07 Å, leads to improve the simulated spectrum with respect to that obtained from the B3LYP force field. For the other open-shell actinyls, [NpO2]2+ and [PuO2]2+, a simplified strategy has been adopted to improve the simulated EXAFS spectrum. It is computed taking as reference structure the NEVPT2 optimized geometry and including the DW factors of their corresponding MD simulations employing the B3LYP force field. A better agreement between the experimental and the simulated EXAFS spectra is found, confirming the a priori guess that the inclusion of dynamic and static correlation refine the structural description of the open-shell actinyl aqua ions.

Extension of the QuickFF force field protocol for an improved accuracy of structural, vibrational, mechanical and thermal properties of metal-organic frameworks.

QuickFF was originally launched in 2015 to derive accurate force fields for isolated and complex molecular systems in a quick and easy way. Apart from the general applicability, the functionality was especially tested for metal-organic frameworks (MOFs), a class of hybrid materials consisting of organic and inorganic building blocks. Herein, we launch a new release of the QuickFF protocol which includes new major features to predict structural, vibrational, mechanical and thermal properties with greater accuracy, without compromising its robustness and transparent workflow. First, the ab initio data necessary for the fitting procedure may now also be derived from periodic models for the molecular system, as opposed to the earlier cluster-based models. This is essential for an accurate description of MOFs with one-dimensional metal-oxide chains. Second, cross terms that couple internal coordinates (ICs) and anharmonic contributions for bond and bend terms are implemented. These features are essential for a proper description of vibrational and thermal properties. Third, the fitting scheme was modified to improve robustness and accuracy. The new features are tested on MIL-53(Al), MOF-5, CAU-13 and NOTT-300. As expected, periodic input data are proven to be essential for a correct description of structural, vibrational and thermodynamic properties of MIL-53(Al). Bulk moduli and thermal expansion coefficients of MOF-5 are very accurately reproduced by static and dynamic simulations using the newly derived force fields which include cross terms and anharmonic corrections. For the flexible materials CAU-13 and NOTT-300, the transition pressure is accurately predicted provided cross terms are taken into account. © 2018 Wiley Periodicals, Inc.

QuickFF: A program for a quick and easy derivation of force fields for metal-organic frameworks from ab initio input.

QuickFF is a software package to derive accurate force fields for isolated and complex molecular systems in a quick and easy manner. Apart from its general applicability, the program has been designed to generate force fields for metal-organic frameworks in an automated fashion. The force field parameters for the covalent interaction are derived from ab initio data. The mathematical expression of the covalent energy is kept simple to ensure robustness and to avoid fitting deficiencies as much as possible. The user needs to produce an equilibrium structure and a Hessian matrix for one or more building units. Afterward, a force field is generated for the system using a three-step method implemented in QuickFF. The first two steps of the methodology are designed to minimize correlations among the force field parameters. In the last step, the parameters are refined by imposing the force field parameters to reproduce the ab initio Hessian matrix in Cartesian coordinate space as accurate as possible. The method is applied on a set of 1000 organic molecules to show the easiness of the software protocol. To illustrate its application to metal-organic frameworks (MOFs), QuickFF is used to determine force fields for MIL-53(Al) and MOF-5. For both materials, accurate force fields were already generated in literature but they requested a lot of manual interventions. QuickFF is a tool that can easily be used by anyone with a basic knowledge of performing ab initio calculations. As a result, accurate force fields are generated with minimal effort. © 2015 Wiley Periodicals, Inc.

GeauxDock: A novel approach for mixed-resolution ligand docking using a descriptor-based force field.

Molecular docking is an important component of computer-aided drug discovery. In this communication, we describe GeauxDock, a new docking approach that builds on the ideas of ligand homology modeling. GeauxDock features a descriptor-based scoring function integrating evolutionary constraints with physics-based energy terms, a mixed-resolution molecular representation of protein-ligand complexes, and an efficient Monte Carlo sampling protocol. To drive docking simulations toward experimental conformations, the scoring function was carefully optimized to produce a correlation between the total pseudoenergy and the native-likeness of binding poses. Indeed, benchmarking calculations demonstrate that GeauxDock has a strong capacity to identify near-native conformations across docking trajectories with the area under receiver operating characteristics of 0.85. By excluding closely related templates, we show that GeauxDock maintains its accuracy at lower levels of homology through the increased contribution from physics-based energy terms compensating for weak evolutionary constraints. GeauxDock is available at http://www.institute.loni.org/lasigma/package/dock/.

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.

Conformational state-specific free energy differences by one-step perturbation: protein secondary structure preferences of the GROMOS 43A1 and 53A6 force fields.

The one-step free energy perturbation approach can be applied to obtain conformational state-specific free energy differences (FEDs) associated with changes in force field parameters, and thus offers the possibility to consider conformational equilibria during force field parameterization. In this work, using the alanine decapeptide in explicit water solution as a model, the α-helical and ß-hairpin state-specific FEDs associated with force field changes between two widely used parameter sets of the GROMOS force field, namely, 43A1 and 53A6, were determined using one-step perturbation. The results mostly deviated by only 1 kJ mol(−1) in absolute or a few percent in relative values from thermodynamic integration results, suggesting that the convergence ranges of one-step perturbation were large enough to cover the substantial changes in nonbonded parameters between the two parameter sets. It was also found that one-step perturbation may give larger errors when the changes from the reference state include a large decrease in van der Waals radius, as indicated by the result for the ß-hairpin state-specific free energy change going from 53A6 to 43A1. According to the free energy results, the α-helical state of the alanine decapeptide is destabilized by 15 kJ mol(−1), i.e., 1.5 kJ mol(−1) per residue, relative to the ß-hairpin state when going from 43A1 to 53A6, in agreement with previous direct simulations in which native α-helices were often found to be unstable in simulations using 53A6, despite that the 53A6 parameters better reproduce a range of thermodynamic properties of small molecular systems. By applying one-step perturbation to analyze the effects of perturbing individual parameters, the differential stabilization of the two secondary structure states can be traced to the changes in van der Waals parameters, especially a van der Waals parameter involved in third-neighbor interactions. This study provides an example of the efficiency of one-step perturbation in force field development, reducing the computational cost by orders of magnitude.

Transferable Molecular Model of Woven Covalent Organic Framework Materials.

Two woven covalent organic framework materials (COF-505 and COF-506) have been synthesized since 2016, and the latter demonstrated the ability to take up dyes and other small molecules. This opens the door to applications such as separations, sensing, and catalysis. However, accelerating the design of future woven materials by changing the chemistry of the "threads" will require a computational model for these materials. Since no such atomic-scale model exists, we have developed a protocol for optimizing a force field for woven materials which can be used as the input to molecular dynamics simulations. Their high density and elasticity made these COFs challenging to model at a semiempirical level. Our modeling approach required simultaneous optimization of lattice parameters and elasticity using density functional theory-derived energy barriers and available experimental results. We used this force field, parameterized to fit COF-505, without change, to predict the structure of COF-506. This model allowed us to predict an anisotropy in 505's elasticity and preferred directions for diffusion which cannot be seen experimentally. The pore size distribution for 506 is dominated by small pores (80% <10 Å dia.), though 5% of the pores are up to 20 Å in diameter. We confirmed the experimental result that gases (barring helium) do not diffuse appreciably in COF-505. We validated our (unaltered) force field model to accurately predict experimental uptake data for tetrahydrofuran and methyl orange dye in COF-506. We proposed an atomic-scale mechanism by which COF-505 becomes metallated and demetallated. In addition, in advance of experimental studies, we determined the ability of 505 to incorporate other metals, such as Zn and Fe, which might be considered artificial photosynthesis agents. These predictions validate that Cu was a particularly appropriate choice of metal center for the synthesis, showcasing the ability of this model to play a role in designing woven materials a priori.

Extension and validation of the GLYCAM force field parameters for modeling glycosaminoglycans.

Glycosaminoglycans (GAGs) are an important class of carbohydrates that serve critical roles in blood clotting, tissue repair, cell migration and adhesion, and lubrication. The variable sulfation pattern and iduronate ring conformations in GAGs influence their polymeric structure and nature of interaction. This study characterizes several heparin-like GAG disaccharides and tetrasaccharides using NMR and molecular dynamics simulations to assist in the development of parameters for GAGs within the GLYCAM06 force field. The force field additions include parameters and charges for a transferable sulfate group for O- and N-sulfation, neutral (COOH) forms of iduronic and glucuronic acid, and Δ4,5-unsaturated uronate (ΔUA) residues. ΔUA residues frequently arise from the enzymatic digestion of heparin and heparin sulfate. Simulations of disaccharides containing ΔUA reveal that the presence of sulfation on this residue alters the relative populations of 1H2 and 2H1 ring conformations. Simulations of heparin tetrasaccharides containing N-sulfation in place of N-acetylation on glucosamine residues influence the ring conformations of adjacent iduronate residues.

Les glycosaminoglycanes (GAG) sont une classe importante d'hydrates de carbone qui jouent un rôle crucial dans la coagulation sanguine, la réparation des tissus, la migration et l'adhérence cellulaires, et la lubrification. La disposition variable des groupes sulfate et la conformation du cycle de l'iduronate des GAG influent sur leur structure polymérique et sur la nature des interactions. Dans la présente étude, nous caractérisons divers GAG disaccharidiques et tétrasaccharidiques semblables à l'héparine par RMN et modélisation de dynamique moléculaire en vue de contribuer à la détermination de paramètres pour les GAG dans le champ de force GLYCAM06. Les éléments additionnels au champ de force comprennent les paramètres et les charges associés à un groupe sulfate transférable lors de la O-sulfatation et de la N-sulfatation, les formes neutres (COOH) des acides iduronique et glucuronique et les résidus uronate Δ4,5-insaturés (ΔUA). Des résidus ΔUA sont souvent formés lors de la digestion enzymatique de l'héparine et du sulfate d'héparine. Des modélisations de disaccharides contenant des ΔUA révèlent que la présence de groupes sulfate sur ces résidus modifie les populations relatives des conformations de cycle 1H2 et 2H1. Les modelisations de tétrasaccharides à base d'héparine présentant une N-sulfatation au lieu d'une N-acétylation des résidus glucosamine influent sur les conformations de cycle des résidus iduronate adjacents. [Traduit par la Rédaction].