Reliable and Accurate Solution to the Induced Fit Docking Problem for Protein-Ligand Binding.

We present a reliable and accurate solution to the induced fit docking problem for protein-ligand binding by combining ligand-based pharmacophore docking, rigid receptor docking, and protein structure prediction with explicit solvent molecular dynamics simulations. This novel methodology in detailed retrospective and prospective testing succeeded to determine protein-ligand binding modes with a root-mean-square deviation within 2.5 Å in over 90% of cross-docking cases.

Simple Predictive Models of Passive Membrane Permeability Incorporating Size-Dependent Membrane-Water Partition.

We investigate the relationship between passive permeability and molecular size, in the context of solubility-diffusion theory, using a diverse compound set with molecular weights ranging from 151 to 828, which have all been characterized in a consistent manner using the RRCK cell monolayer assay. Computationally, each compound was subjected to extensive conformational search and physics-based permeability prediction, and multiple linear regression analyses were subsequently performed to determine, empirically, the relative contributions of hydrophobicity and molecular size to passive permeation in the RRCK assay. Additional analyses of Log D and PAMPA data suggest that these measurements are not size selective, a possible reason for their sometimes weak correlation with cell-based permeability.

A 3D-RISM/RISM study of the oseltamivir binding efficiency with the wild-type and resistance-associated mutant forms of the viral influenza B neuraminidase.

The binding affinity of oseltamivir to the influenza B neuraminidase and to its variants with three single substitutions, E119G, R152K, and D198N, is investigated by the MM/3D-RISM method. The binding affinity or the binding free energy of ligand to receptor was found to be determined by a subtle balance of two major contributions that largely cancel out each other: the ligand-receptor interactions and the dehydration free energy. The theoretical results of the binding affinity of the drug to the mutants reproduced the observed trend in the resistivity, measured by IC50 ; the high-level resistance of E119G and R152K, and the low-level resistance of D198N.

Cavity as a source of conformational fluctuation and high-energy state: high-pressure NMR study of a cavity-enlarged mutant of T4 lysozyme.

Although the structure, function, conformational dynamics, and controlled thermodynamics of proteins are manifested by their corresponding amino acid sequences, the natural rules for molecular design and their corresponding interplay remain obscure. In this study, we focused on the role of internal cavities of proteins in conformational dynamics. We investigated the pressure-induced responses from the cavity-enlarged L99A mutant of T4 lysozyme, using high-pressure NMR spectroscopy.

Determination of the formylglycinamide ribonucleotide amidotransferase ammonia pathway by combining 3D-RISM theory with experiment.

Molecular tunnels in enzyme systems possess variable architecture and are therefore difficult to predict. In this work, we design and apply an algorithm to resolve the pathway followed by ammonia using the bifunctional enzyme formylglycinamide ribonucleotide amidotransferase (FGAR-AT) as a model system. Though its crystal structure has been determined, an ammonia pathway connecting the glutaminase domain to the 30 Å distal FGAR/ATP binding site remains elusive.

Analysis of biomolecular solvation sites by 3D-RISM theory.

We derive, implement, and apply equilibrium solvation site analysis for biomolecules. Our method utilizes 3D-RISM calculations to quickly obtain equilibrium solvent distributions without either necessity of simulation or limits of solvent sampling. Our analysis of these distributions extracts highest likelihood poses of solvent as well as localized entropies, enthalpies, and solvation free energies.

Towards an understanding of channelrhodopsin function: simulations lead to novel insights of the channel mechanism.

Channelrhodopsins (ChRs) are light-gated cation channels that mediate ion transport across membranes in microalgae (vectorial catalysis). ChRs gain increasing attention as useful tools for the analysis of neural networks in tissues and living animals (optogenetics). In fact, various mutagenesis approaches have realized practical applications with high reliability by enhancement of the expression level, channel kinetics control, and color tuning.

Placevent: an algorithm for prediction of explicit solvent atom distribution-application to HIV-1 protease and F-ATP synthase.

We have created a simple algorithm for automatically predicting the explicit solvent atom distribution of biomolecules. The explicit distribution is coerced from the three-dimensional (3D) continuous distribution resulting from a 3D reference interaction site model (3D-RISM) calculation. This procedure predicts optimal location of solvent molecules and ions given a rigid biomolecular structure and the solvent composition.

Exchange Often and Properly in Replica Exchange Molecular Dynamics.

Previous work by us showed that in replica exchange molecular dynamics, exchanges should be attempted extremely often, providing gains in efficiency and no undesired effects. Since that time some questions have been raised about the extendability of these claims to the general case. In this work, we answer this question in two ways.

Apo and nickel-bound forms of the Pyrococcus horikoshii species of the metalloregulatory protein: NikR characterized by molecular dynamics simulations.

NikR is a homotetrameric nickel regulatory protein whose binding to free Ni(2+) increases its binding affinity for a gene that codes for a nickel transporter protein. It is comprised of a tetrameric nickel-binding domain, flanked by two dimeric DNA-binding domains. Though X-ray crystallography data for various species (Escherichia coli, Heliobacter pylori, and Pyrococcus horikoshii) of NikR reveal large conformational differences between nickel-bound, DNA-bound, and unbound forms, transitions between them have never been observed.

Bad Seeds Sprout Perilous Dynamics: Stochastic Thermostat Induced Trajectory Synchronization in Biomolecules.

Molecular dynamics simulations starting from different initial conditions are commonly used to mimic the behavior of an experimental ensemble. We show in this article that when a Langevin thermostat is used to maintain constant temperature during such simulations, extreme care must be taken when choosing the random number seeds to prevent statistical correlation among the MD trajectories. While recent studies have shown that stochastically thermostatted trajectories evolving within a single potential basin with identical random number seeds tend to synchronize, we show that there is a synchronization effect even for complex, biologically relevant systems.

Exchange frequency in replica exchange molecular dynamics.

The effect of the exchange-attempt frequency on sampling efficiency is studied in replica exchange molecular dynamics (REMD). We show that sampling efficiency increases with increasing exchange-attempt frequency. This conclusion is contrary to a commonly expressed view in REMD.