Molecular simulation methods for conformational searches and diffusivity

Abstract

Computer modeling is a powerful technique to provide explanations and make predictions in drug development using computational methods. Molecular conformations affect drug binding and biological activity, so the preferred conformation of a drug molecule plays an important role in design and synthesis of new drugs. We have developed a conformational search method to automatically identify low energy conformations of drug molecules in an explicit solvent. This method uses replica-exchange molecular dynamics and clustering analysis to efficiently sample conformational space and identify the most probable conformations. The method produces distinct primary conformations for a molecule in explicit solvent, implicit solvent, and gas phase. Drug development is also concerned with membrane permeation. Many drugs have intracellular targets, and the rate and mechanism of membrane permeation affects their biological behavior. Transmembrane diffusion coefficients can be calculated using Generalized Langevin methods. We have compared the velocity autocorrelation and the position autocorrelation methods using molecular dynamics simulations of various solutes in homogeneous liquids, and of a water molecule harmonically restrained at various points within a lipid bilayer. Our results indicate that known limitations when using the position autocorrelation function can potentially be resolved using the velocity autocorrelation function. The effects of the spring constant and the choice of thermostat on both methods are also discussed.