Virtual‐system‐coupled adaptive umbrella sampling to compute free‐energy landscape for flexible molecular docking

A novel enhanced conformational sampling method, virtual‐system‐coupled adaptive umbrella sampling (V‐AUS), was proposed to compute 300‐K free‐energy landscape for flexible molecular docking, where a virtual degrees of freedom was introduced to control the sampling. This degree of freedom interacts with the biomolecular system. V‐AUS was applied to complex formation of two disordered amyloid‐β (Aβ_30–35) peptides in a periodic box filled by an explicit solvent. An interpeptide distance was defined as the reaction coordinate, along which sampling was enhanced. A uniform conformational distribution was obtained covering a wide interpeptide distance ranging from the bound to unbound states. The 300‐K free‐energy landscape was characterized by thermodynamically stable basins of antiparallel and parallel β‐sheet complexes and some other complex forms. Helices were frequently observed, when the two peptides contacted loosely or fluctuated freely without interpeptide contacts. We observed that V‐AUS converged to uniform distribution more effectively than conventional AUS sampling did. © 2015 Wiley Periodicals, Inc.