pPerturb: A Server for Predicting Long-Distance Energetic Couplings and Mutation-Induced Stability Changes in Proteins via Perturbations

Abstract

The strength of intraprotein interactions or contact network is one of the dominant factors determining the thermodynamic stabilities of proteins. The nature and the extent of connectivity of this network also play a role in allosteric signal propagation characteristics upon ligand binding to a protein domain. Here, we develop a server for rapid quantification of the strength of an interaction network by employing an experimentally consistent perturbation approach previously validated against a large data set of 375 mutations in 19 different proteins. The web server can be employed to predict the extent of destabilization of proteins arising from mutations in the protein interior in experimentally relevant units. Moreover, coupling distancesa measure of the extent of percolation on perturbationand overall perturbation magnitudes are predicted in a residue-specific manner, enabling a first look at the distribution of energetic couplings in a protein or its changes upon ligand binding. We show specific examples of how the server can be employed to probe for the distribution of local stabilities in a protein, to examine changes in side chain orientations or packing before and after ligand binding, and to predict changes in stabilities of proteins upon mutations of buried residues. The web server is freely available at http://pbl. biotech.iitm.ac.in/pPerturb and supports recent versions of all major browsers.

Probing structural basis for enhanced binding of SARS‐CoV‐2 P.1 variant spike protein with the human ACE2 receptor

“…PRS was performed using the pPerturb server 45 . It allows the mutation of one or more residues to alanine and generates a perturbation profile (∆Q vs. Calpha‐Calpha) distance from the perturb site.…”

Exploring Mechanisms of Communication Switching in the Hsp90-Cdc37 Regulatory Complexes with Client Kinases through Allosteric Coupling of Phosphorylation Sites: Perturbation-Based Modeling and Hierarchical Community Analysis of Residue Interaction Networks

“…To compare different network-based approaches, we also explored a recently proposed structural perturbation approach for determining the extent of allosteric coupling and strength of allosteric interaction networks. , In this approach, the perturbation involves the alanine mutation of a given site while maintaining two shells of interaction around the perturbed residue. Using the pPerturb server for predicting mutation-induced allosteric changes in proteins, we computed the residue-based profile that estimates the number of perturbed network interactions caused by the mutated site (Figure ). A rapid alanine scanning of the protein residues in the Hsp90-Cdc37-Cdk4 complex produced effective perturbation profiles showing that mutations in the regulatory phosphorylation sites of the Hsp90 could induce a significant long-range effect (Figure A,B).…”

Web-based tools for computational enzyme design

“…Although it is not devoted to enzyme engineering per se, it can provide comprehensive structural knowledge. pPerturb [34] aims primarily at assessing the importance of different residues to the stability by analyzing the effects of alanine mutations on the global number of contacts in the structure. The workflow is divided into perturbation profiles calculation (ΔQ), interaction networks, and the change in thermodynamic stability from truncating side chains.…”