Representations Of Protein Structure For Exploring The Conformational Space: A Speed-Accuracy Trade-Off

The recent breakthrough in the field of protein structure prediction shows the relevance of using knowledge-based based scoring functions in combination with a low-resolution 3D representation of protein macromolecules. The choice of not using all atoms is barely supported by any data in the literature, and is mostly motivated by empirical and practical reasons, such as the computational cost of assessing the numerous folds of the protein conformational space. Here, we present a comprehensive study, carried on a large and balanced benchmark of predicted protein structures, to see how different types of structural representations rank in either accuracy or calculation speed, and which ones offer the best compromise between these two criteria. We tested ten representations, including low-resolution, high-resolution, and coarse-grained approaches. We also investigated the generalization of the findings to other formalisms than the widely-used "potential of mean force" (PMF) method. Thus, we observed that representing protein structures by their beta carbons-combined or not with C alpha-provides the best speed-accuracy trade-off, when using a "total information gain" scoring function. For statistical PMFs, using MARTINI backbone and side-chains beads is the best option. Finally, we also demonstrated the necessity of training the reference state on all atom types, and of including the C alpha atoms of glycine residues, in a C beta-based representation. (C) 2021 The Authors. Published by Elsevier B.V. on behalf of Research Network of Computational and Structural Biotechnology.