Exploring the potential of a structural alphabet-based tool for mining multiple target conformations and target flexibility insight

Abstract

Protein flexibility is often implied in binding with different partners and is essential for protein function. The growing number of macromolecular structures in the Protein Data Bank entries and their redundancy has become a major source of structural knowledge of the protein universe. The analysis of structural variability through available redundant structures of a target, called multiple target conformations (MTC), obtained using experimental or modeling methods and under different biological conditions or different sources is one way to explore protein flexibility. This analysis is essential to improve the understanding of various mechanisms associated with protein target function and flexibility. In this study, we explored structural variability of three biological targets by analyzing different MTC sets associated with these targets. To facilitate the study of these MTC sets, we have developed an efficient tool, SA-conf, dedicated to capturing and linking the amino acid and local structure variability and analyzing the target structural variability space. The advantage of SA-conf is that it could be applied to divers sets composed of MTCs available in the PDB obtained using NMR and crystallography or homology models. This tool could also be applied to analyze MTC sets obtained by dynamics approaches. Our results showed that SA-conf tool is effective to quantify the structural variability of a MTC set and to localize the structural variable positions and regions of the target. By selecting adapted MTC subsets and comparing their variability detected by SA-conf, we highlighted different sources of target flexibility such as induced by binding partner, by mutation and intrinsic flexibility. Our results support the interest to mine available structures associated with a target using to offer valuable insight into target flexibility and interaction mechanisms. The SA-conf executable script, with a set of pre-compiled binaries are available at http://www.mti.univ-paris-diderot.fr/recherche/plateformes/logiciels.

Impacts of drug resistance mutations on the structural asymmetry of the HIV-2 protease

“…In contrast, our results identified 25 residues that were characterized as asymmetric in the three minimized wild-type structures and overrepresented in terms of asymmetry in the mutant structures. Twelve of these 25 asymmetric positions (18,42,50,51,59, 60, 64, 75, 77, 83, 92, and 93) were previously detected as overrepresented in terms of asymmetry in the 19 PR2 structures available in the PDB [31]. These results confirm that the backbone asymmetry of these residues is important for PR2 structure and function [31].…”

“…All these results confirm that backbone asymmetry is an intrinsic property of PR2 that is involved in its flexibility and ligand recognition and binding. They also confirm the interest in mining several structures associated with a target to offer valuable insight into target structure, flexibility and interaction mechanisms [40][41][42].…”

Characterization of HIV-2 Protease Structure by Studying Its Asymmetry at the Different Levels of Protein Description

“…Four structural-letter couples (X-T, X-N, X-S, and V-A) are observed only at asym Struct positions putatively induced by crystallization that suggests that crystal packing is responsible for these particular deformations. This indicates that the crystallization method could produce particular local conformations as it was previously observed for nuclear magnetic resonance method [31]. However, as these couples were weakly observed, this result must be taken with caution.…”

SAFlex: A structural alphabet extension to integrate protein structural flexibility and missing data information

“…However, it also shows its limits in case of conformation plasticity. In this case, the independent chain encodings can be carrefully explored to detect variable positions and SL changes potentially due to intrinsic flexilibity, to partner binding or to sequence mutation effects [ 25 ].…”

“…They have been applied in the past to protein structure analysis, including multiple structure alignment, structure mining [ 16 , 17 ], protein fold classification [ 18 ], dynamic molecular analysis [ 19 – 21 ], structure fast comparison [ 17 ] and generation of 3D peptide conformations [ 22 , 23 ]. The SA approach also appears to be promising to characterize structural variability [ 24 , 25 ], to explore the local backbone deformation involved in protein-protein interactions [ 26 , 27 ] and to predict local protein flexibility [ 28 , 29 ].…”