Biomolecular simulation is increasingly central to understanding and designing biological molecules and their interactions. Detailed, physics‐based simulation methods are demonstrating rapidly growing impact in areas as diverse as biocatalysis, drug delivery, biomaterials, biotechnology, and drug design. Simulations offer the potential of uniquely detailed, atomic‐level insight into mechanisms, dynamics, and processes, as well as increasingly accurate predictions of molecular properties. Simulations can now be used as computational assays of biological activity, for example, in predictions of drug resistance. Methodological and algorithmic developments, combined with advances in computational hardware, are transforming the scope and range of calculations. Different types of methods are required for different types of problem. Accurate methods and extensive simulations promise quantitative comparison with experiments across biochemistry. Atomistic simulations can now access experimentally relevant timescales for large systems, leading to a fertile interplay of experiment and theory and offering unprecedented opportunities for validating and developing models. Coarse‐grained methods allow studies on larger length‐ and timescales, and theoretical developments are bringing electronic structure calculations into new regimes. Multiscale methods are another key focus for development, combining different levels of theory to increase accuracy, aiming to connect chemical and molecular changes to macroscopic observables. In this review, we outline biomolecular simulation methods and highlight examples of its application to investigate questions in biology.This article is categorized under: Molecular and Statistical Mechanics > Molecular Dynamics and Monte‐Carlo Methods Structure and Mechanism > Computational Biochemistry and Biophysics Molecular and Statistical Mechanics > Free Energy Methods

The transmembrane permeation of eight small (molecular weight <100) organic molecules across a phospholipid bilayer is investigated by multiscale molecular dynamics simulation. The bilayer and hydrating water are represented by simplified, efficient coarse-grain models, whereas the permeating molecules are described by a standard atomic-level force-field. Permeability properties are obtained through a refined version of the z-constraint algorithm. By constraining each permeant at selected depths inside the bilayer, we have sampled free energy differences and diffusion coefficients across the membrane. These data have been combined, according to the inhomogeneous solubility−diffusion model, to yield the permeability coefficients. The results are generally consistent with previous atomic-level calculations and available experimental data. Computationally, our multiscale approach proves 2 orders of magnitude faster than traditional atomic-level methods.

The unassisted permeation process of β-blocker drugs (alprenolol, atenolol, pindolol) and steroid hormones (progesterone, testosterone) through a lipid membrane is simulated by a novel dual-resolution molecular dynamics approach. The lipid and water molecules are described by simple and efficient coarse-grain models, whereas the drug and hormone permeants are represented by traditional atomistic models. Our hybrid method is about two orders of magnitude faster than standard atomic-level counterparts. For each permeant, we calculate the transfer free energy as a function of depth inside the bilayer; these data indicate the location across the membrane where the solutes preferentially partition. Using the free energy profiles, we develop a simple expression that proves remarkably accurate in predicting experimental permeability rankings; the proposed permeation model highlights and addresses potentially problematic aspects of the standard solubility-diffusion theory. We also calculate the diffusion coefficients of the permeants, and track their lateral motion to study their diffusive patterns. Furthermore, we show the drugs' perturbing effect on the bilayer structure and quantify the steroids' preferred orientations. The results obtained compare favourably with experimental measurements and traditional atomic-level simulation data reported in the literature. Promising potential applications of our methodology to areas such as drug design and membrane-protein modelling are discussed.