Division of Structural Biology and Bioinformatics, CSIR-Indian Institute of Chemical Biology, Kolkata, India.
Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, India.
FEBS Lett. 2021 Feb;595(4):442-451. doi: 10.1002/1873-3468.14038. Epub 2021 Jan 31.
The pathogenesis of the SARS-CoV-2 virus initiates through recognition of the angiotensin-converting enzyme 2 (ACE2) receptor of the host cells by the receptor-binding domain (RBD) located at the spikes of the virus. Here, using molecular dynamics simulations, we have demonstrated the allosteric crosstalk within the RBD in the apo- and the ACE2 receptor-bound states, revealing the contribution of the dynamics-based correlated motions and the electrostatic energy perturbations to this crosstalk. While allostery, based on correlated motions, dominates inherent distal communication in the apo-RBD, the electrostatic energy perturbations determine favorable pairwise crosstalk within the RBD residues upon binding to ACE2. Interestingly, the allosteric path is composed of residues which are evolutionarily conserved within closely related coronaviruses, pointing toward the biological relevance of the communication and its potential as a target for drug development.
新冠病毒的发病机制始于病毒刺突上的受体结合域（RBD）识别宿主细胞的血管紧张素转换酶 2（ACE2）受体。在这里，我们通过分子动力学模拟，展示了 RBD 在无配体和与 ACE2 受体结合状态下的变构串扰，揭示了基于动力学的相关运动和静电能扰动对此串扰的贡献。虽然基于相关运动的变构作用主导了无配体 RBD 中的固有远程通讯，但静电能扰动决定了与 ACE2 结合时 RBD 残基内有利的成对串扰。有趣的是，变构途径由在密切相关的冠状病毒中进化保守的残基组成，这表明通讯具有生物学相关性，并且可能成为药物开发的靶点。
