Protein Flexibility in In Silico Screening

Abstract

We summarize computational approaches in structure‐based ligand design (SBLD) and in silico screening that address issues of protein flexibility and mobility. In particular, we consider how protein plasticity can be incorporated into docking strategies. As a first requirement, one needs to detect what can move and how. Moving protein parts can be identified from experimental information as well as established computational techniques such as molecular dynamics (MD) simulations, graph theoretical and geometry‐based approaches, or harmonic analysis‐based methods. Second, this knowledge needs to be transformed into a docking algorithm. A multitude of approaches considering protein mobility has been introduced recently, with motions modeled either implicitly or explicitly. In the latter case, one can further distinguish between modeling of side‐chain‐only motions and motions including backbone changes. In all cases, accuracy needs to be balanced against efficiency. Case studies for which the inclusion of protein plasticity was crucial to success are noted along these lines. This allows us to identify scope and limitations of the current approaches, as well as guidelines for further developments.