Macromolecular dynamics manifest as disorder in structure determination, which is subsequently accounted for by displacement parameters (also called temperature factors, or B-factors) or alternate conformations. Though B-factors contain detailed information about structural dynamics, they are the total of multiple sources of disorder, making them difficult to interpret and thus little-used in structural analysis. We report here an analytical approach for decomposing molecular disorder into a parsimonious hierarchical series of contributions, providing an intuitive basis for quantitative structural-dynamics analysis. We demonstrate the decomposition of disorder on example SARS-CoV-2 and STEAP4 structures, from both crystallographic and cryo-electron microscopy data, and reveal how understanding of the macromolecular disorder leads to deeper understanding of molecular motions and flexibility, and suggests hypotheses for molecular mechanisms.
Bibliographical noteFunding Information:
N.M.P. recognises funding from a long-term fellowship from the European Molecular Biology Organisation (EMBO), fellowship number ALTF 609-2017, and from a Veni Fellowship, fellowship number VI.Veni.192.143 from the Dutch Research Council (NWO). P.G. recognises funding from the Dutch Research Council (NWO), project number 01.80.104.00. N.M.P. thanks Helen Ginn, Billy Poon, and James Parkhurst for their help and guidance with c++ and cctbx. N.M.P. and P.G. thank Wout Oosterheert for discussions of the STEAP structures, the coronavirus structural task force (inside-corona.net) for discussions of the SARS-CoV-2 structures, and Loes Kroon-Batenburg, Tim de Klijn and Jitse van der Horn for general discussions regarding disorder. N.M.P. is especially grateful to Arwen Pearson for her invaluable and indefatigable support.
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