phenix.ensemble_refinement: a test study of apo and holo BACE1

Abstract

phenix.ensemble_refinement (Burnley et al. 2012) combines molecular dynamic (MD) simulations with X-­‐ray structure refinement to generate ensemble models fitted to diffraction data. It is an evolution of the ‘time-­‐averaging’ method first proposed by Gros et al. in 1990 (Gros, van Gunsteren, and Hol 1990) and now utilizes a maximum-­‐likelihood target function, a dual explicit-­‐bulk solvent model and introduces a TLS fitting procedure that absorbs rigid-­‐body motions such that short MD simulations can be used to sample local disorder. The resulting ensemble model represents, as a Boltzmann-­‐ weighted population of structures, the simulation trajectory and provides implicit modeling of anisotropic and anharmonic motions. This family of structures provides two main advantages: 1) a reduction in Rfree compared with traditional single structure models and 2) quantification and visualization of protein dynamics that have been demonstrated to correlate with biological function. Methodological implementation and testing is described in detail in Burnley et al. 2012; here we focus on a practical usage of the method.