Perturb–Scan–Pull: A Novel Method Facilitating Conformational Transitions in Proteins

Abstract

Conformational transitions in proteins facilitate precise physiological functions. Therefore, it is crucial to understand the mechanisms underlying these processes to modulate protein function. Yet, studying structural and dynamical properties of proteins is notoriously challenging due to the complexity of the underlying potential energy surfaces (PES). We have previously developed the perturbation-response scanning (PRS) method to identify key residues that participate in the communication network responsible for specific conformational transitions. PRS is based on a residue-by-residue scan of the protein to determine the subset of residues/forces which provide the closest conformational change leading to a target conformational state, inasmuch as linear response theory applies to these motions. Here, we develop a novel method to further evaluate if conformational transitions may be triggered on the PES. We aim to study functionally relevant conformational transitions in proteins by using results obtained from PRS and feeding them as inputs to steered molecular dynamics simulations. The success and the transferability of the method are evaluated on three protein systems having different complexities of motion on the PES: calmodulin, adenylate kinase, and bacterial ferric binding protein. We find that the method captures the target conformation, while providing key residues and the optimum paths with relatively low free energy profiles.

Molecular Simulations and Network Modeling Reveal an Allosteric Signaling in the SARS-CoV-2 Spike Proteins

“… 83 − 89 The PRS approach can also be efficiently combined with the dynamic analysis of residue interaction networks to identify and characterize allosteric hotspots and pathways of allosteric communications. 85 − 91 By monitoring the response to forces on the protein residues, the PRS approach can quantify allosteric couplings and link the directionality of the inserted force to the protein response in functional movements. 90 , 91 In the PRS approach, the 3 N × 3 N Hessian matrix H of the second derivatives of the potential at the local minimum is computed.…”

“… 85 − 91 By monitoring the response to forces on the protein residues, the PRS approach can quantify allosteric couplings and link the directionality of the inserted force to the protein response in functional movements. 90 , 91 In the PRS approach, the 3 N × 3 N Hessian matrix H of the second derivatives of the potential at the local minimum is computed. The 3 N -dimensional vector Δ R of node displacements in response to the 3 N -dimensional perturbation force is evaluated according to Hooke’s law F = H * Δ R .…”

Fast and exact single and double mutation-response scanning of proteins

“…This numerical method proceeds as follows. For each site j, M random forces are generated following (6) and 7, the corresponding structural responses are calculated using (8), and averaged over mutations to calculate S ij , according to (10).…”

“…[3][4][5][6][7] Conformational deformations due to protein-ligand binding have been modelled using external forces applied locally to the superficial residues known or presumed to be involved in binding. 4,7 This has proved useful for a number of applications such as predicting ligand-induced deformations, 4,7,8 predicting ligand-binding sites related to known or desired deformations, 9,10 and studying allosteric communication. [11][12][13] Similar perturbation approaches focused on the structural response to mutations have been used for analysing pathological mutations 14,15 and understanding patterns of protein evolution 6,14,16,17 The previous simulation-based approaches may become too computationally costly to deal with very large systems, such as supra-molecular complexes, like a ribosome or a virus capsid.…”

A Coarse-Grained Methodology Identifies Intrinsic Mechanisms That Dissociate Interacting Protein Pairs

“…PRS serves as a tool to gain insight into molecular origins of mechanical feedbacks of bimolecular structures through recording response to each inserted force on each residue of a protein ( Atilgan and Atilgan, 2009 ; Atilgan et al, 2010a , 2011 ; Abdizadeh et al, 2015b ; Abdizadeh and Atilgan, 2016 ). It is further capable of recognizing how directionality of the inserted force may coordinate the response of the protein in a functional motion ( Jalalypour et al, 2020 ). PRS requires two distinct conformations of a protein, determined, e.g., by x-ray crystallography, as input; and relies on LRT to relate virtual external forces acting on a protein to the perturbed positions of the residues ( Ikeguchi et al, 2005 ).…”