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The Local Topological Free Energy of the SARS-CoV-2 Spike Protein.

ABSTRACT: The novel coronavirus SARS-CoV-2 infects human cells using a mechanism that involves binding and structural rearrangement of its Spike protein. Understanding protein rearrangement and identifying specific amino acids where mutations affect protein rearrangement has attracted much attention for drug development. In this manuscript, we use a mathematical method to characterize the local topology/geometry of the SARS-CoV-2 Spike protein backbone. Our results show that local conformational changes in the FP, HR1, and CH domains are associated with global conformational changes in the RBD domain. The SARS-CoV-2 variants analyzed in this manuscript (alpha, beta, gamma, delta Mink, G614, N501) show differences in the local conformations of the FP, HR1, and CH domains as well. Finally, most mutations of concern are either in or in the vicinity of high local topological free energy conformations, suggesting that high local topological free energy conformations could be targets for mutations with significant impact of protein function. Namely, the residues 484, 570, 614, 796, and 969, which are present in variants of concern and are targeted as important in protein function, are predicted as such from our model.

SUBMITTER: Baldwin Q

PROVIDER: S-EPMC9332627 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Activation Pathways and Free Energy Landscapes of the SARS-CoV-2 Spike Protein.

Project description:Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) uses a spike protein (S-protein) to recognize the receptor protein ACE2 of human cells and initiate infection, during which the conformational transition of the S-protein from inactive (down) state to active (up) state is one of the key molecular events determining the infectivity but the underlying mechanism remains poorly understood. In this work, we investigated the activation pathways and free energy landscape of the S-protein of SARS-CoV-2 and compared with those of the closely related counterpart SARS-CoV using molecular dynamics simulations. Our results revealed a large difference between the activation pathways of the two S-proteins. The transition from inactive to an active state for the S-protein of SARS-CoV-2 is more cooperative, involving simultaneous disruptions of several key interfacial hydrogen bonds, and the transition encounters a much higher free energy barrier. In addition, the conformational equilibrium of the SARS-CoV-2 S-protein is more biased to the inactive state compared to that of the SARS-CoV S-protein, suggesting the transient feature of the active state before binding to the receptor protein of the host cell. The key interactions contributing to the difference of the activation pathways and free energy landscapes were discussed. The results provide insights into the molecular mechanism involved in the initial stage of the SARS-CoV-2 infection.

| S-EPMC8424691 | biostudies-literature

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