Kinematic Flexibility Analysis: Hydrogen Bonding Patterns Impart a Spatial Hierarchy of Protein Motion

Journal of Chemical Information and Modeling
Dominik BuddayHenry van den Bedem

Abstract

Elastic network models (ENMs) and constraint-based, topological rigidity analysis are two distinct, coarse-grained approaches to study conformational flexibility of macromolecules. In the two decades since their introduction, both have contributed significantly to insights into protein molecular mechanisms and function. However, despite a shared purpose of these approaches, the topological nature of rigidity analysis, and thereby the absence of motion modes, has impeded a direct comparison. Here, we present an alternative, kinematic approach to rigidity analysis, which circumvents these drawbacks. We introduce a novel protein hydrogen bond network spectral decomposition, which provides an orthonormal basis for collective motions modulated by noncovalent interactions, analogous to the eigenspectrum of normal modes. The zero modes decompose proteins into rigid clusters identical to those from topological rigidity, while nonzero modes rank protein motions by their hydrogen bond collective energy penalty. Our kinematic flexibility analysis bridges topological rigidity theory and ENM, enabling a detailed analysis of motion modes obtained from both approaches. Analysis of a large, structurally diverse data set revealed that collectiv...Continue Reading

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Citations

Jul 6, 2019·Journal of Synchrotron Radiation·Henry van den Bedem, Mark A Wilson
Dec 6, 2019·Proceedings of the National Academy of Sciences of the United States of America·Medhanjali DasguptaMark A Wilson

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