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- Title
Mixed mechanism of conformational selection and induced fit as a molecular recognition process in the calreticulin family of proteins.
- Authors
Mamidi, Ashalatha Sreshty; Surolia, Avadhesha
- Abstract
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. Author summary: Conformational dynamics impact molecular recognition. Understanding the time dependent fluctuations in the atomic coordinates of the biomolecules may assist in capturing their diverse structural configurations. There are several theories of molecular recognition like lock-and-key model, induced fit and conformational selection that are hypothesized to explain the protein-ligand, protein-protein, protein-DNA, protein-RNA and RNA-ligand interactions participating in signaling, catalysis, gene regulation, and protein aggregation in health and disease. Nevertheless, very few studies have been reported on lectin-glycan binding reactions. Hence, we illustrate the basis of molecular recognition underlying lectin-glycan interactions by exploring the structural specificity of calreticulin family of chaperones, which specifically recognize and selectively bind to the monoglucosylated-N-glycan, among an existing pool of various high-mannose oligosaccharides in the endoplasmic reticulum. We performed molecular dynamics simulations to capture the complete conformational space represented by an ensemble of structures for distinct conformations. Structural evidences of distinct conformations of lectins in free and bound forms were characterized through free energy of binding, non-covalent interactions, protein-surface topography mapped by physicochemical properties like electrostatic and hydrophobic potentials to highlight and correlate the structural differences with the biomolecular behavior during binding. From this study, we noticed that both conformational selection and induced fit play a critical role in selective binding of the monoglucosylated-N-glycan and thus propose a mixed mechanism of binding in the calreticulin family of proteins.
- Subjects
MOLECULAR recognition; GLYCANS; MOLECULAR dynamics; CALRETICULIN; LECTINS; MOLECULAR theory; MOLECULAR interactions
- Publication
PLoS Computational Biology, 2022, Vol 18, Issue 12, p1
- ISSN
1553-734X
- Publication type
Article
- DOI
10.1371/journal.pcbi.1010661