Atom-centered Partial Charges Research Articles

PyRESP: A Program for Electrostatic Parameterizations of Additive and Induced Dipole Polarizable Force Fields.

Molecular modeling at the atomic level has been applied in a wide range of biological systems. The widely adopted additive force fields typically use fixed atom-centered partial charges to model electrostatic interactions. However, the additive force fields cannot accurately model polarization effects, leading to unrealistic simulations in polarization-sensitive processes. Numerous efforts have been invested in developing induced dipole-based polarizable force fields. Whether additive atomic charge models or polarizable induced dipole models are used, proper parameterization of the electrostatic term plays a key role in the force field developments. In this work, we present a Python program called PyRESP for performing atomic multipole parameterizations by reproducing ab initio electrostatic potential (ESP) around molecules. PyRESP provides parameterization schemes for several electrostatic models, including the RESP model with atomic charges for the additive force fields and the RESP-ind and RESP-perm models with additional induced and permanent dipole moments for the polarizable force fields. PyRESP is a flexible and user-friendly program that can accommodate various needs during force field parameterizations for molecular modeling of any organic molecules.

PyRESP: A flexible program for polarizable force field parameterizations

Molecular modeling on atomic level have been applied in a wide range of biological systems. The widely adopted additive force fields typically use fixed atom-centered partial charges to model electrostatic interactions. However, the additive force fields cannot accurately model polarization effects, leading to unrealistic simulations in polarization sensitive processes. Numerous attempts have been directed to developing induced dipole based polarizable models, including the Applequist point dipole model, the Thole damped dipole model, and the recently proposed polarizable Gaussian multipole (pGM) model.

W-RESP: Well-Restrained Electrostatic Potential-Derived Charges. Revisiting the Charge Derivation Model

Representation of electrostatic interactions by a Coulombic pairwise potential between atom-centered partial charges is a fundamental and crucial part of empirical force fields used in classical molecular dynamics simulations. The broad success of the AMBER force-field family originates mainly from the restrained electrostatic potential (RESP) charge model, which derives partial charges to reproduce the electrostatic field around the molecules. However, the description of the electrostatic potential around molecules by standard RESP may be biased for some types of molecules. In this study, we modified the RESP charge derivation model to improve its description of the electrostatic potential around molecules and thus electrostatic interactions in the force field. In particular, we reoptimized the atomic radii for definition of the grid points around the molecule, redesigned the restraining scheme, and included extra point (EP) charges. The RESP fitting was significantly improved for aromatic heterocyclic molecules. Thus, the suggested W-RESP(-EP) charge derivation model shows some potential for improving the performance of the nucleic acid force fields, for which the poor description of nonbonded interactions, such as the underestimated stability of base pairing, is well-established. We also report some preliminary simulation tests (around 1 ms of simulation data) on A-RNA duplexes, tetranucleotides, and tetraloops. The simulations reveal no adverse effects, while the description of base-pairing interactions might be improved. The new charges can thus be used in future attempts to improve the nucleic acid simulation force fields, in combination with reparametrization of the other terms.

Exponential repulsion improves structural predictability of molecular docking.

Molecular docking is a powerful tool for theoretical prediction of the preferred conformation and orientation of small molecules within protein active sites. The obtained poses can be used for estimation of binding energies, which indicate the inhibition effect of designed inhibitors, and therefore might be used for in silico drug design. However, the evaluation of ligand binding affinity critically depends on successful prediction of the native binding mode. Contemporary docking methods are often based on scoring functions derived from molecular mechanical potentials. In such potentials, nonbonded interactions are typically represented by electrostatic interactions between atom-centered partial charges and standard 6-12 Lennard-Jones potential. Here, we present implementation and testing of a scoring function based on more physically justified exponential repulsion instead of the standard Lennard-Jones potential. We found that this scoring function significantly improved prediction of the native binding modes in proteins bearing narrow active sites such as serine proteases and kinases. © 2016 Wiley Periodicals, Inc.

Averaged Solvent Embedding Potential Parameters for Multiscale Modeling of Molecular Properties.

We derive and validate averaged solvent parameters for embedding potentials to be used in polarizable embedding quantum mechanics/molecular mechanics (QM/MM) molecular property calculations of solutes in organic solvents. The parameters are solvent-specific atom-centered partial charges and isotropic polarizabilities averaged over a large number of geometries of solvent molecules. The use of averaged parameters reduces the computational cost to obtain the embedding potential, which can otherwise be a rate-limiting step in calculations involving large environments. The parameters are evaluated by analyzing the quality of the resulting molecular electrostatic potentials with respect to full QM potentials. We show that a combination of geometry-specific parameters for solvent molecules close to the QM region and averaged parameters for solvent molecules further away allows for efficient polarizable embedding multiscale modeling without compromising the accuracy. The results are promising for the development of general embedding parameters for biomolecules, where the reduction in computational cost can be considerable.

Multi-layer coarse-graining polarization model for treating electrostatic interactions of solvated α-conotoxin peptides

A multi-layer coarse-graining (CG) model is presented for treating the electrostatic interactions of solvated α-conotoxin peptides. According to the sensitivity to the electrostatic environment, a hybrid set of electrostatic parameters, such as secondary-structure- and residue-based dipoles, and atom-centered partial charges, are adopted. For the polarization "inert" secondary-structures and residues, the fragment dipole moments are distributed within narrow ranges with the magnitude close to zero. The coarse-graining fragment dipoles are parameterized from a large training set (10,000 configurations) to reproduce the electrostatic features of molecular fragments. In contrast, the electrostatically "sensitive" atoms exhibit large fluctuations of charges with the varied environments. The environment-dependent variable charges are updated in each energetic calculation. The electrostatic interaction of the whole chemical system is hence partitioned into several sub-terms coming from the fragment dipole-dipole, (fragment) dipole-(atom) charge, and atom charge-charge interactions. A large number of test calculations on the relative energies of cyclo-peptide conformers have demonstrated that the multi-layer CG electrostatic model presents better performance than the non-polarized force fields, in comparison with the density-functional theory and the fully polarized force field model. The selection of CG fragment centers, mass or geometric center, has little influence on the fragment-based dipole-dipole interactions. The multi-layer partition of electrostatic polarization is expected to be applied to many biologically interesting and complicated phenomena.

Ab Initio Quantum Mechanical Study of Metal Substitution in Analogues of Rubredoxin: Implications for Redox Potential Control

Substitution of different metals into the redox sites of metalloproteins is a means of studying the structure of the native protein and of varying the redox properties of the protein. The implicit assumption is often made that metal substitution changes only intrinsic properties of the redox site such as the ionization potential without altering the surrounding protein or solvent. However, if this is not true, structural studies of metal-substituted proteins will not reflect the native protein and the differences in redox potential upon metal substitution will not be simply the differences in ionization potential of the redox sites because of perturbations in the extrinsic electric field. Here, we present an ab initio unrestricted Hartree−Fock quantum mechanical study of metal substitution in the [M(SCH3)4)]2-/1- analogue, where M = Fe, Co, Ni, and Zn, of the protein rubredoxin. Variations in several physical properties were determined and compared to experimental data. Upon metal substitution, only minor variations in geometry, atomic spin, and atom-centered partial charges of the redox site are observed. However, significant variation is found in the energies of reduction, on the order of 100−1000 mV. This indicates that when such substitutions are made into an Fe−S metalloprotein, little change will occur in the interactions between the metal site and the surrounding protein and thus the surrounding protein structure and the resultant electric field will not change. Thus, the structure is relevant to the native protein and the redox properties are mainly determined by the variations in the intrinsic ionization potential of the metal site and not the extrinsic field of the surrounding protein and solvent.

Calculation of atom-centered partial charges for heme

Atom-centered partial charges are calculated for the Fe-heme in cytochrome P450cam for use in molecular dynamics simulations of polar substrates bound in the active site of the enzyme. Charges are fit to the electrostatic potential produced by ab initio UHF wavefunctions for an Fe-porphine model. Basis set dependence of these charges is observed using the LANL1DZ, LANL2DZ and augmented 6–31G levels of theory. Upon geometry optimization of the enzyme, these charge sets cause varying degrees of distortion of the porphyrin from its crystallographically observed conformation. Scaling the charges calculated from the augmented 6–31G basis by 75% reduces the heme distortion while preserving reasonable interactions with a polar substrate. A comparison of the calculated charges with other published values is presented.

A simple approach to electronic charge induction in atomistic simulations

A scheme is presented for periodically updating atom-centered partial charges due to changing local electric fields that arise during the course of a molecular simulation. The effects of electrostatic induction, due to polarization of the local electron density of bonded atom pairs, are realized through the approximation of the bond polarizability tensor as being cylindrically symmetric and directed along the bond axis, with negligible lateral polarizability. This simplification allows the reduction of polarization effects to a scalar bond ‘polarization parameter’, and subsequent partitioning of the local electron density into charge modifiers located at atom centers. The induced charges assigned to each atom are determined self-consistently. This simplification permits a reasonable approximation of both the magnitude and direction of molecular dipole moments and of molecular polarizabilities in the case of small-molecule fluorocarbons. The model is extended to the calculation of atom-centered partial atomic charges for two conformations of poly(vinylidenefluoride). The proposed method fits well into the framework of established atomistic simulation techniques based on Coulombic nonbonded atomic interactions.

An Electrostatic Induction Model for Fluoroalkane Polymers

ABSTRACTAn electrostatic induction model based on atom-centered partial charges is presented. In this representation, the local electric field is evaluated at each bond center. The bonds are treated as entities polarizable only in a direction parallel to the bond itself by means of a scalar bond polarization parameter. The resulting induced charge separation contributes to the local electric field experienced by neighboring bonds, resulting in a final set of charges which are calculated self-consistently. The model provides a reasonable approximation to dipole moment vectors and polarizabilities of small molecule fluoroalkanes. The results are discussed in comparison with other induction models. This model fits well into the framework of established atomistic potential energy calculations using an atom-centered partial charge representation.