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Pharmaceuticals 2018, 11(1), 29; doi:10.3390/ph11010029

Heterodimer Binding Scaffolds Recognition via the Analysis of Kinetically Hot Residues

1
Big Blue Genomics, Vojvode Brane 32, 11000 Belgrade, Serbia
2
Department of Chemistry, New York University, 1001 Silver, 100 Washington Square East, New York, NY 10003, USA
Received: 27 December 2017 / Revised: 6 March 2018 / Accepted: 8 March 2018 / Published: 16 March 2018
(This article belongs to the Special Issue Chemoinformatics and Drug Design)
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Abstract

Physical interactions between proteins are often difficult to decipher. The aim of this paper is to present an algorithm that is designed to recognize binding patches and supporting structural scaffolds of interacting heterodimer proteins using the Gaussian Network Model (GNM). The recognition is based on the (self) adjustable identification of kinetically hot residues and their connection to possible binding scaffolds. The kinetically hot residues are residues with the lowest entropy, i.e., the highest contribution to the weighted sum of the fastest modes per chain extracted via GNM. The algorithm adjusts the number of fast modes in the GNM’s weighted sum calculation using the ratio of predicted and expected numbers of target residues (contact and the neighboring first-layer residues). This approach produces very good results when applied to dimers with high protein sequence length ratios. The protocol’s ability to recognize near native decoys was compared to the ability of the residue-level statistical potential of Lu and Skolnick using the Sternberg and Vakser decoy dimers sets. The statistical potential produced better overall results, but in a number of cases its predicting ability was comparable, or even inferior, to the prediction ability of the adjustable GNM approach. The results presented in this paper suggest that in heterodimers at least one protein has interacting scaffold determined by the immovable, kinetically hot residues. In many cases, interacting proteins (especially if being of noticeably different sizes) either behave as a rigid lock and key or, presumably, exhibit the opposite dynamic behavior. While the binding surface of one protein is rigid and stable, its partner’s interacting scaffold is more flexible and adaptable. View Full-Text
Keywords: protein-protein interactions; normal mode analysis; Gaussian Network Model; protein decoys protein-protein interactions; normal mode analysis; Gaussian Network Model; protein decoys
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This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. (CC BY 4.0).

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Perišić, O. Heterodimer Binding Scaffolds Recognition via the Analysis of Kinetically Hot Residues. Pharmaceuticals 2018, 11, 29.

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