Jumping between protein conformers using normal modes.

The relationship between the normal modes of a protein and its functional conformational change has been studied for decades. However, using this relationship in a predictive context remains a challenge. In this work, we demonstrate that, starting from a given protein conformer, it is possible to generate in a single step model conformers that are less than 1 Å (Cα -RMSD) from the conformer which is the known endpoint of the conformational change, particularly when the conformational change is collective in nature. Such accurate model conformers can be generated by following either the so-called robust or the 50 lowest-frequency modes obtained with various Elastic Network Models (ENMs). Interestingly, the quality of many of these models compares well with actual crystal structures, as assessed by the ROSETTA scoring function and PROCHECK. The most accurate and best quality conformers obtained in the present study were generated by using the 50 lowest-frequency modes of an all-atom ENM. However, with less than ten robust modes, which are identified without any prior knowledge of the nature of the conformational change, nearly 90% of the motion described by the 50 lowest-frequency modes of a protein can be captured. Such results strongly suggest that exploring the robust modes of ENMs may prove efficient for sampling the functionally relevant conformational repertoire of many proteins. © 2017 Wiley Periodicals, Inc.