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Mixed mechanism of conformational selection and induced fit as a molecular recognition process in the calreticulin family of proteins

Mamidi, AS and Surolia, A (2022) Mixed mechanism of conformational selection and induced fit as a molecular recognition process in the calreticulin family of proteins. In: PLoS Computational Biology, 18 (12).

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Official URL: https://doi.org/10.1371/journal.pcbi.1010661


The fundamental question on the mechanism of molecular recognition during ligand binding has attracted a lot of scientific scrutiny. The two competing theories of ligand binding–“induced fit” and “conformational selection” have been proposed to explain biomolecular recognition. Since exploring a family of proteins with similar structural architectures and conserved functional roles can provide valuable insight into the significance of molecular structure and function, we performed molecular dynamics simulations on the calreticulin family of proteins, which specifically recognize monoglucosylated N-glycan during the protein folding process. Atomistic simulations of lectins in free and bound forms demonstrated that they exist in several conformations spanning from favorable to unfavorable for glycan binding. Our analysis was confined to the carbohydrate recognition domain (CRD) of these lectins to demonstrate the degree of conservation in protein sequence and structure and relate them with their function. Furthermore, we computed the lectin-glycan binding affinity using the mmPBSA approach to identify the most favorable lectin conformation for glycan binding and compared the molecular interaction fields in terms of noncovalent bond interactions. We also demonstrated the involvement of Tyr and Trp residues in the CRD with the non-reducing end glucose and central mannose residues, which contribute to some of the specific interactions. Furthermore, we analyzed the conformational changes in the CRD through SASA, RMSFs and protein surface topography mapping of electrostatic and hydrophobic potentials. Our findings demonstrate a hybrid mechanism of molecular recognition, initially driven by conformational selection followed by glycan-induced fluctuations in the key residues to strengthen the glycan binding interactions. © 2022 Mamidi, Surolia. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Item Type: Journal Article
Publication: PLoS Computational Biology
Publisher: Public Library of Science
Additional Information: The copyright for this article belongs to the Authors.
Keywords: Binding energy; Ligands; Molecular dynamics; Molecular recognition; Molecular structure; Polysaccharides; Topography, Biomolecular recognition; Calreticulin; Carbohydrate-recognition domains; Conformational selection; Glycans; Induced fit; Ligand binding; Mixed mechanisms; Recognition process; Structural architecture, Proteins, carbohydrate; lectin; ligand; polysaccharide; protein binding, binding site; chemistry; molecular dynamics, Binding Sites; Carbohydrates; Lectins; Ligands; Molecular Dynamics Simulation; Polysaccharides; Protein Binding
Department/Centre: Division of Biological Sciences > Molecular Biophysics Unit
Date Deposited: 27 Jan 2023 09:38
Last Modified: 27 Jan 2023 09:38
URI: https://eprints.iisc.ac.in/id/eprint/79558

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