Abstract

BackgroundThe architectural organization of protein structures has been the focus of intense research since it can hopefully lead to an understanding of how proteins fold. In earlier works we had attempted to identify the inherent structural organization in proteins through a study of protein topology. We obtained a modular partitioning of protein structures with the modules correlating well with experimental evidence of early folding units or “foldons”. Residues that connect different modules were shown to be those that were protected during the transition phase of folding.Methodology/Principal FindingsIn this work, we follow the topological path of ubiquitin through molecular dynamics unfolding simulations. We observed that the use of recurrence quantification analysis (RQA) could lead to the identification of the transition state during unfolding. Additionally, our earlier contention that the modules uncovered through our graph partitioning approach correlated well with early folding units was vindicated through our simulations. Moreover, residues identified from native structure as connector hubs and which had been shown to be those that were protected during the transition phase of folding were indeed more stable (less flexible) well beyond the transition state. Further analysis of the topological pathway suggests that the all pairs shortest path in a protein is minimized during folding.ConclusionsWe observed that treating a protein native structure as a network by having amino acid residues as nodes and the non-covalent interactions among them as links allows for the rationalization of many aspects of the folding process. The possibility to derive this information directly from 3D structure opens the way to the prediction of important residues in proteins, while the confirmation of the minimization of APSP for folding allows for the establishment of a potentially useful proxy for kinetic optimality in the validation of sequence-structure predictions.

Highlights

  • There has been renewed interest in understanding the structural and architectural organization of proteins through a network representation of proteins

  • We observed that treating a protein native structure as a network by having amino acid residues as nodes and the non-covalent interactions among them as links allows for the rationalization of many aspects of the folding process

  • The possibility to derive this information directly from 3D structure opens the way to the prediction of important residues in proteins, while the confirmation of the minimization of all pairs shortest path (APSP) for folding allows for the establishment of a potentially useful proxy for kinetic optimality in the validation of sequence-structure predictions

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Summary

Introduction

There has been renewed interest in understanding the structural and architectural organization of proteins through a network representation of proteins. Ever since Anfinsen’s experiment in 1973 [1] proved that all the information for a protein to fold into its three dimensional structure is encoded in its primary sequence, many models have been developed based on a host of theoretical, simulated or experimental techniques [2]. The chief among these are the nucleation-propagation model [3,4], the nucleation-condensation model [5], the sequential and hierarchical model [6], the collapse model [7] and the modular model [8,9,10,11]. Residues that connect different modules were shown to be those that were protected during the transition phase of folding

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