Force Field for Mg(2+), Mn(2+), Zn(2+), and Cd(2+) Ions That Have Balanced Interactions with Nucleic Acids.

Divalent metal ions are of fundamental importance to the function and folding of nucleic acids. Divalent metal ion-nucleic acid interactions are complex in nature and include both territorial and site specific binding. Commonly employed nonbonded divalent ion models, however, are often parametrized against bulk ion properties and are subsequently utilized in biomolecular simulations without considering any data related to interactions at specific nucleic acid sites.

Competitive interaction of monovalent cations with DNA from 3D-RISM.

The composition of the ion atmosphere surrounding nucleic acids affects their folding, condensation and binding to other molecules. It is thus of fundamental importance to gain predictive insight into the formation of the ion atmosphere and thermodynamic consequences when varying ionic conditions. An early step toward this goal is to benchmark computational models against quantitative experimental measurements.

Comparison of structural, thermodynamic, kinetic and mass transport properties of Mg(2+) ion models commonly used in biomolecular simulations.

The prevalence of Mg(2+) ions in biology and their essential role in nucleic acid structure and function has motivated the development of various Mg(2+) ion models for use in molecular simulations. Currently, the most widely used models in biomolecular simulations represent a nonbonded metal ion as an ion-centered point charge surrounded by a nonelectrostatic pairwise potential that takes into account dispersion interactions and exchange effects that give rise to the ion's excluded volume. One strategy toward developing improved models for biomolecular simulations is to first identify a Mg(2+) model that is consistent with the simulation force fields that closely reproduces a range of properties in aqueous solution, and then, in a second step, balance the ion-water and ion-solute interactions by tuning parameters in a pairwise fashion where necessary.

Multiscale methods for computational RNA enzymology.

RNA catalysis is of fundamental importance to biology and yet remains ill-understood due to its complex nature. The multidimensional "problem space" of RNA catalysis includes both local and global conformational rearrangements, changes in the ion atmosphere around nucleic acids and metal ion binding, dependence on potentially correlated protonation states of key residues, and bond breaking/forming in the chemical steps of the reaction. The goal of this chapter is to summarize and apply multiscale modeling methods in an effort to target the different parts of the RNA catalysis problem space while also addressing the limitations and pitfalls of these methods.

Multipolar Ewald methods, 2: applications using a quantum mechanical force field.

A fully quantum mechanical force field (QMFF) based on a modified “divide-and-conquer” (mDC) framework is applied to a series of molecular simulation applications, using a generalized Particle Mesh Ewald method extended to multipolar charge densities. Simulation results are presented for three example applications: liquid water, p-nitrophenylphosphate reactivity in solution, and crystalline N,N-dimethylglycine. Simulations of liquid water using a parametrized mDC model are compared to TIP3P and TIP4P/Ew water models and experiment.

Multipolar Ewald methods, 1: theory, accuracy, and performance.

The Ewald, Particle Mesh Ewald (PME), and Fast Fourier–Poisson (FFP) methods are developed for systems composed of spherical multipole moment expansions. A unified set of equations is derived that takes advantage of a spherical tensor gradient operator formalism in both real space and reciprocal space to allow extension to arbitrary multipole order. The implementation of these methods into a novel linear-scaling modified “divide-and-conquer” (mDC) quantum mechanical force field is discussed.

A variational linear-scaling framework to build practical, efficient next-generation orbital-based quantum force fields.

We introduce a new hybrid molecular orbital/density-functional modified divide-and-conquer (mDC) approach that allows the linear-scaling calculation of very large quantum systems. The method provides a powerful framework from which linear-scaling force fields for molecular simulations can be developed. The method is variational in the energy, and has simple, analytic gradients and essentially no break-even point with respect to the corresponding full electronic structure calculation.

Direct observations of shifts in the β-sheet register of a protein-peptide complex using explicit solvent simulations.

Using explicit solvent molecular dynamics simulations, we were able to obtain direct observations of shifts in the hydrogen-bonding register of an intermolecular β-sheet protein-peptide complex. The β-sheet is formed between the FHA domain of cancer marker protein Ki67 (Ki67FHA) and a peptide fragment of the hNIFK signaling protein. Potential encounter complexes of the Ki67FHA receptor and hNIFK peptide are misregistered states of the β-sheet.