J. Chem. Theory Comput. 2010, 6, 3285–3292 3285 Using Selectively Applied Accelerated Molecular Dynamics to Enhance Free Energy Calculations Jeff Wereszczynski* and J. Andrew McCammon The Department of Chemistry and Biochemistry, UniVersity of California, San Diego, 9500 Gilman DriVe, La Jolla, California 92093, United States Received June 11, 2010 Abstract: Accelerated molecular dynamics (aMD) has been shown to enhance conformational space sampling relative to classical molecular dynamics; however, the exponential reweighting of aMD trajectories, which is necessary for the calculation of free energies relating to the classical system, is oftentimes problematic, especially for systems larger than small poly peptides. Here, we propose a method of accelerating only the degrees of freedom most pertinent to sampling, thereby reducing the total acceleration added to the system and improving the convergence of calculated ensemble averages, which we term selective aMD. Its application is highlighted in two biomolecular cases. First, the model system alanine dipeptide is simulated with classical MD, all-dihedral aMD, and selective aMD, and these results are compared to the inﬁnite sampling limit as calculated with metadynamics. We show that both forms of aMD enhance the convergence of the underlying free energy landscape by 5-fold relative to classical MD; however, selective aMD can produce improved statistics over all-dihedral aMD due to the improved reweighting. Then we focus on the pharmaceutically relevant case of computing the free energy of the decoupling of oseltamivir in the active site of neuraminidase. Results show that selective aMD greatly reduces the cost of this alchemical free energy transformation, whereas all-dihedral aMD produces unreliable free energy estimates. 1. Introduction Molecular dynamics (MD) simulations have become a crucial theoretical tool in advancing our understanding of the function of biological macromolecules.1 Advances in algo- rithms2 and computing power3-5 continue to allow for simulations of increasingly larger systems on longer and longer time scales, permitting the direct observation of all- atom protein folding,6,7 the observation of ion permeation through a transmembrane channel,8 and the simulation of a complete virus.9 Despite the remarkable progress that has been made in the ﬁeld, simulation times still often fall far short of the miscosecond to millisecond time scales inherent in many biological processes. There have been several methodological advances which have aimed at simulating longer time scales within current computational power such as implicit solvation models,10 multiple time stepping algo- rithms,11 and improved treatment of long-range electrostat- * Corresponding author e-mail: jmweresz@mccammon.ucsd.edu. ics.12 Sampling of phase space may also be enhanced through the deformation of the underlying potential energy surface,13 as has been done in hyperdynamics,14 puddle jumping,15 conformational ﬂooding,16 and the local boost method17 (to name only a few). Our group recently developed a method to enhance the crossing of barriers and the sampling of phase space termed accelerated molecular dynamics (aMD),18 which has been shown to enhance sampling of biomolecular systems as in the conformational switching of Ras,19 improve the agreement between experimental and calculated chemical shifts for IκBR,20 and accelerate the calculation of pKa values in lysozyme.21 An area of particular interest concerns using aMD simula- tions to calculate ensemble averages for physically relevant nonaccelerated systems. For systems in which the energy added to accelerate the system is low, trajectories may easily be reweighted; however, as the system size increases the boost energy required for signiﬁcant acceleration increases, causing the exponential reweighting factor to produce 10.1021/ct100322t  2010 American Chemical Society Published on Web 10/13/2010