A chemical potential equalization method for molecular simulations

A formulation of the chemical potential ͑electronegativity͒ equalization principle is presented from the perspective of density-functional theory. The resulting equations provide a linear-response framework for describing the redistribution of electrons upon perturbation by an applied field. The method has two main advantages over existing electronegativity equalization and charge equilibration methods that allow extension to accurate molecular dynamics simulations. Firstly, the expansion of the energy is taken about the molecular ground state instead of the neutral atom ground states; hence, in the absence of an external field, the molecular charge distribution can be represented by static point charges and dipoles obtained from fitting to high-level ab initio calculations without modification. Secondly, in the presence of applied fields or interactions with other molecules, the density response can be modeled accurately using basis functions. Inclusion of basis functions with dipolar or higher order multipolar character allows molecules or chemical groups to have correct local anisotropic polarizabilities. A modified semiempirical form of the hardness matrix has been introduced that can be evaluated efficiently using Gaussians, and requires only one parameter per basis function. Applications at two basis-set levels demonstrate the method can accurately reproduce induced dipole moments and estimated chemical potentials obtained from density-functional calculations for a variety of molecules. Inclusion of basis functions beyond the conventional spherical-atom type is essential in some instances. The present formulation provides the foundation for a promising semi-empirical model for polarization and charge transfer in molecular simulations

The contribution of phosphate–phosphate repulsions to the free energy of DNA bending

DNA bending is important for the packaging of genetic material, regulation of gene expression and interaction of nucleic acids with proteins. Consequently, it is of considerable interest to quantify the energetic factors that must be overcome to induce bending of DNA, such as base stacking and phosphate–phosphate repulsions. In the present work, the electrostatic contribution of phosphate–phosphate repulsions to the free energy of bending DNA is examined for 71 bp linear and bent-form model structures. The bent DNA model was based on the crystallographic structure of a full turn of DNA in a nucleosome core particle. A Green's function approach based on a linear-scaling smooth conductor-like screening model was applied to ascertain the contribution of individual phosphate–phosphate repulsions and overall electrostatic stabilization in aqueous solution. The effect of charge neutralization by site-bound ions was considered using Monte Carlo simulation to characterize the distribution of ion occupations and contribution of phosphate repulsions to the free energy of bending as a function of counterion load. The calculations predict that the phosphate–phosphate repulsions account for ∼30% of the total free energy required to bend DNA from canonical linear B-form into the conformation found in the nucleosome core particle

Catalytic mechanism and pH dependence of a methyltransferase ribozyme (MTR1) from computational enzymology

A methyltransferase ribozyme (MTR1) was selected in vitro to catalyze alkyl transfer from exogenous O6-methylguanine (O6mG) to a target adenine N1, and recently, high-resolution crystal structures have become available. We use a combination of classical molecular dynamics, ab initio quantum mechanical/molecular mechanical (QM/MM) and alchemical free energy (AFE) simulations to elucidate the atomic-level solution mechanism of MTR1. Simulations identify an active reactant state involving protonation of C10 that hydrogen bonds with O6mG:N1. The deduced mechanism involves a stepwise mechanism with two transition states corresponding to proton transfer from C10:N3 to O6mG:N1 and rate-controlling methyl transfer (19.4  kcal·mol-1 barrier). AFE simulations predict the pKa for C10 to be 6.3, close to the experimental apparent pKa of 6.2, further implicating it as a critical general acid. The intrinsic rate derived from QM/MM simulations, together with pKa calculations, enables us to predict an activity-pH profile that agrees well with experiment. The insights gained provide further support for a putative RNA world and establish new design principles for RNA-based biochemical tools.</p

Influence of C-5 substituted cytosine and related nucleoside analogs on the formation of benzo[a]pyrene diol epoxide-dG adducts at CG base pairs of DNA

Endogenous 5-methylcytosine (MeC) residues are found at all CG dinucleotides of the p53 tumor suppressor gene, including the mutational ‘hotspots' for smoking induced lung cancer. MeC enhances the reactivity of its base paired guanine towards carcinogenic diolepoxide metabolites of polycyclic aromatic hydrocarbons (PAH) present in cigarette smoke. In the present study, the structural basis for these effects was investigated using a series of unnatural nucleoside analogs and a representative PAH diolepoxide, benzo[a]pyrene diolepoxide (BPDE). Synthetic DNA duplexes derived from a frequently mutated region of the p53 gene (5′-CCCGGCACCC GC[15N3,13C1-G]TCCGCG-3′, + strand) were prepared containing [15N3, 13C1]-guanine opposite unsubstituted cytosine, MeC, abasic site, or unnatural nucleobase analogs. Following BPDE treatment and hydrolysis of the modified DNA to 2′-deoxynucleosides, N2-BPDE-dG adducts formed at the [15N3, 13C1]-labeled guanine and elsewhere in the sequence were quantified by mass spectrometry. We found that C-5 alkylcytosines and related structural analogs specifically enhance the reactivity of the base paired guanine towards BPDE and modify the diastereomeric composition of N2-BPDE-dG adducts. Fluorescence and molecular docking studies revealed that 5-alkylcytosines and unnatural nucleobase analogs with extended aromatic systems facilitate the formation of intercalative BPDE-DNA complexes, placing BPDE in a favorable orientation for nucleophilic attack by the N2 position of guanin

DeePMD-kit v2: A software package for Deep Potential models

DeePMD-kit is a powerful open-source software package that facilitates molecular dynamics simulations using machine learning potentials (MLP) known as Deep Potential (DP) models. This package, which was released in 2017, has been widely used in the fields of physics, chemistry, biology, and material science for studying atomistic systems. The current version of DeePMD-kit offers numerous advanced features such as DeepPot-SE, attention-based and hybrid descriptors, the ability to fit tensile properties, type embedding, model deviation, Deep Potential - Range Correction (DPRc), Deep Potential Long Range (DPLR), GPU support for customized operators, model compression, non-von Neumann molecular dynamics (NVNMD), and improved usability, including documentation, compiled binary packages, graphical user interfaces (GUI), and application programming interfaces (API). This article presents an overview of the current major version of the DeePMD-kit package, highlighting its features and technical details. Additionally, the article benchmarks the accuracy and efficiency of different models and discusses ongoing developments.Comment: 51 pages, 2 figure

Improvement of semiempirical response properties with charge-dependent response density Magnetic linear response properties calculations with the Gaussian and augmented-plane-wave method LocalSCF method for semiempirical quantum-chemical calculation of ul

Articles you may be interested in The present work outlines a new method for treatment of charge-dependent polarizability in semiempirical quantum models for use in combined quantum-mechanical/molecular mechanical simulations of biological reactions. The method addresses a major shortcoming in the performance of conventional semiempirical models for these simulations that is tied to the use of a localized minimal atomic-orbital basis set. The present approach has the advantages that it uses a density basis that retains a set of linear-response equations, does not increase the atomic-orbital basis, and avoids the problem of artificial charge transfer and scaling of the polarizability seen in related models that allow atomic charges to fluctuate. The model introduces four new atom-based parameters and has been tested with the modified neglect of differential overlap d-orbital Hamiltonian against 1132 molecules and ions and shown to decrease the dipole moment and polarizability errors by factors of 2 and 10, respectively, with respect to density-functional results. The method performs impressively for a variety of charge states ͑from 2+ to 2−͒, and offers a potentially powerful extension in the design of next generation semiempirical quantum models for accurate simulations of highly charged biological reactions

Examination of the correlation energy and second virial coefficients from accurate ab initio calculations of rare-gas dimers The accuracy of ab initio molecular geometries for systems containing second-row atoms Accuracy of spectroscopic constants of diat

Articles you may be interested in Anharmonic rovibrational calculations of singlet cyclic C4 using a new ab initio potential and a quartic force field J. Chem. Phys. 139, 22430