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Perturbation of ACE2 Structural Ensembles by SARS-CoV-2 Spike Protein Binding.

ABSTRACT: The human ACE2 enzyme serves as a critical first recognition point of coronaviruses, including SARS-CoV-2. In particular, the extracellular domain of ACE2 interacts directly with the S1 tailspike protein of the SARS-CoV-2 virion through a broad protein-protein interface. Although this interaction has been characterized by X-ray crystallography, these structures do not reveal significant differences in the ACE2 structure upon S1 protein binding. In this work, using several all-atom molecular dynamics simulations, we show persistent differences in the ACE2 structure upon binding. These differences are determined with the linear discriminant analysis (LDA) machine learning method and validated using independent training and testing datasets, including long trajectories generated by D. E. Shaw Research on the Anton 2 supercomputer. In addition, long trajectories for 78 potent ACE2-binding compounds, also generated by D. E. Shaw Research, were projected onto the LDA classification vector in order to determine whether the ligand-bound ACE2 structures were compatible with S1 protein binding. This allows us to predict which compounds are "apo-like" versus "complex-like" and to pinpoint long-range ligand-induced allosteric changes in the ACE2 structure.

SUBMITTER: Uyar A

PROVIDER: S-EPMC8370119 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:MOTIVATION:The recent emergence of the novel SARS-coronavirus 2 (SARS-CoV-2) and its international spread pose a global health emergency. The spike (S) glycoprotein binds ACE2 and promotes SARS-CoV-2 entry into host cells. The trimeric S protein binds the receptor using the receptor-binding domain (RBD) causing conformational changes in S protein that allow priming by host cell proteases. Unraveling the dynamic structural features used by SARS-CoV-2 for entry might provide insights into viral transmission and reveal novel therapeutic targets. Using structures determined by X-ray crystallography and cryo-EM, we performed structural analysis and atomic comparisons of the different conformational states adopted by the SARS-CoV-2-RBD. RESULTS:Here, we determined the key structural components induced by the receptor and characterized their intramolecular interactions. We show that ?-helix (polyproline-II) is a predominant structure in the binding interface and in facilitating the conversion to the active form of the S protein. We demonstrate a series of conversions between switch-like ?-helix and ?-strand, and conformational variations in a set of short ?-helices which affect the hinge region. These conformational changes lead to an alternating pattern in conserved disulfide bond configurations positioned at the hinge, indicating a possible disulfide exchange, an important allosteric switch implicated in viral entry of various viruses, including HIV and murine coronavirus. The structural information presented herein enables to inspect and understand the important dynamic features of SARS-CoV-2-RBD and propose a novel potential therapeutic strategy to block viral entry. Overall, this study provides guidance for the design and optimization of structure-based intervention strategies that target SARS-CoV-2. AVAILABILITY:We have implemented the proposed methods in an R package freely available at https://github.com/Grantlab/bio3d. SUPPLEMENTARY INFORMATION:Supplementary data are available at Bioinformatics online.

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Perturbation of ACE2 Structural Ensembles by SARS-CoV-2 Spike Protein Binding.

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