Predicting Protein Functional Motions: an Old Recipe with a New Twist

Abstract

Large macromolecules, including proteins and their complexes, very often adopt multiple conformations. Some of them can be seen experimentally, for example with X-ray crystallography or cryo-electron microscopy. This structural heterogeneity is not occasional and is frequently linked with specific biological function. Thus, the accurate description of macromolecular conformational transitions is crucial for understanding fundamental mechanisms of life's machinery. We report on a real-time method to predict such transitions by extrapolating from instantaneous eigen-motions, computed using the normal mode analysis, to a series of twists. We demonstrate the applicability of our approach to the prediction of a wide range of motions, including large collective opening-closing transitions and conformational changes induced by partner binding. We also highlight particularly difficult cases of very small transitions between crystal and solution structures. Our method guaranties preservation of the protein structure during the transition and allows to access conformations that are unreachable with classical normal mode analysis. We provide practical solutions to describe localized motions with a few low-frequency modes and to relax some geometrical constraints along the predicted transitions. This work opens the way to the systematic description of protein motions, whatever their degree of collectivity. Our method is available as a part of the NOn-Linear rigid Block (NOLB) package at https://team.inria.fr/nano-d/software/ nolb-normal-modes/.

Interdomain Flexibility within NADPH Oxidase Suggested by SANS Using LMNG Stealth Carrier

“…This software can rapidly generate a multitude of models along the slowest normal modes computed for the starting structure (32), calculate their scattering curves, and compare them with experimental data (after smearing them by the instrumental resolution). Its approach follows the observation that most protein functional motions can be well described with just a few collective coordinates computed using the normal mode analysis (43). Adapted from Pepsi-SAXS (31) to SANS data (absolute intensity and experimental smearing), Pepsi-SANS software can be downloaded at https://team.inria.fr/nano-d/software/pepsi-sans/ or used online at https:// pepsi.app.ill.fr/ to calculate scattering profiles from a crystallographic structure or model in pdb format.…”

Structures of a deAMPylation complex rationalise the switch between antagonistic catalytic activities of FICD

“…3 , as indicated). Note, the utility of NOLB NMA has recently been demonstrated in both its ability to capture biologically relevant collective as well as localised protein transitions present in solution structures (and not captured in crystallo) without perturbing local protein geometry 60 .…”

HOPMA: Boosting protein functional dynamics with colored contact maps

“…This is particularly visible when predicting a conformational transition from a closed to an open state. Indeed, opening the protein is significantly more difficult than closing it (3, 68). Lowering the distance cutoff used to determine whether two atoms are connected in the network may help to partially solve the problem.…”

“…Complications may arise, for example, from asymmetries in the definition of the network (70). Another strategy consists in updating the elastic network iteratively, either by re-building a network from a conformation obtained by deforming the initial network (68, 71), or by modifying the equilibrium distances on-the-fly, for example to fit the network into a low-resolution map (18, 72).…”

“…NOLB is computationally very efficient, as it can be applied to systems as large as viral capsids or ribosomes at all-atom resolution on a personal laptop (82). It produces conformations with high stereochemical quality and is able to predict motions with different degrees of collectivity, from localized and disruptive motions to highly collectives ones (68). We place ourself in the context where we know the target structure and we use this knowledge to determine the amplitudes of the initial structure’s normal modes.…”