The Center of Excellence in Computational Chemistry, Department of Chemistry, Faculty of Science, Chulalongkorn University, Bangkok 10330, Thailand.
School of Mathematics and Natural Sciences, University of Southern Mississippi, Hattiesburg, MS 39406, USA.
Biophys Chem. 2022 Aug;287:106829. doi: 10.1016/j.bpc.2022.106829. Epub 2022 May 19.
The viral main protease (M) from a novel severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) is a key enzyme essential for viral replication and has become an attractive target for antiviral drug development. The M forms a functional dimer and exhibits a pH-dependent enzyme activity and dimerization. Here, we report a molecular dynamics (MD) investigation to gain insights into the structural stability of the enzyme dimer at neutral and acidic pH. Our data shows larger changes in structure of the protein with the acidic pH than that with the neutral pH. Structural analysis of MD trajectories reveals a substantial increase in intersubunit separation, the loss of domain contacts, binding free energy and interaction energy of the dimer which implies the protein instability and tendency of dimer dissociation at acidic pH. The loss in the interaction energy is mainly driven by electrostatic interactions. We have identified the intersubunit hydrogen-bonding residues involved in the decreased dimer stability. These findings may be helpful for rational drug design and target evaluation against COVID-19.
新型严重急性呼吸综合征冠状病毒 2（SARS-CoV-2）的病毒主要蛋白酶（M）是病毒复制所必需的关键酶，已成为抗病毒药物开发的有吸引力的靶标。M 形成功能性二聚体，并表现出 pH 依赖性的酶活性和二聚化。在这里，我们报告了一项分子动力学（MD）研究，以深入了解酶二聚体在中性和酸性 pH 值下的结构稳定性。我们的数据表明，与中性 pH 值相比，酸性 pH 值下蛋白质结构的变化更大。对 MD 轨迹的结构分析揭示了亚基间分离的显著增加，结构域接触的丧失，二聚体的结合自由能和相互作用能的丧失，这意味着在酸性 pH 值下蛋白质不稳定，二聚体解离的趋势。相互作用能的损失主要是由静电相互作用驱动的。我们已经确定了参与降低二聚体稳定性的亚基间氢键残基。这些发现可能有助于针对 COVID-19 的合理药物设计和靶标评估。
