A multi-resolution model to capture both global fluctuations of an enzyme and molecular recognition in the ligand-binding site

In multi-resolution simulations, different system components are simultaneously modeled at different levels of resolution, these being smoothly coupled together. In the case of enzyme systems, computationally expensive atomistic detail is needed in the active site to capture the chemistry of ligand binding. Global properties of the rest of the protein also play an essential role, determining the structure and fluctuations of the binding site; however, these can be modeled on a coarser level. Similarly, in the most computationally efficient scheme only the solvent hydrating the active site requires atomistic detail. We present a methodology to couple atomistic and coarse-grained protein models, while solvating the atomistic part of the protein in atomistic water. This allows a free choice of which protein and solvent degrees of freedom to include atomistically. This multi-resolution methodology can successfully model stable ligand binding, and we further confirm its validity by exploring the reproduction of system properties relevant to enzymatic function. In addition to a computational speedup, such an approach can allow the identification of the essential degrees of freedom playing a role in a given process, potentially yielding new insights into biomolecular function. Proteins 2016; 84:1902-1913. (c) 2016 Wiley Periodicals, Inc.