High-throughput molecular dynamics-based alchemical free energy calculations for predicting the binding free energy change associated with the common mutations in the spike receptor-binding domain of SARS-CoV-2

Author:

Bhadane RajendraORCID,Salo-Ahen Outi M. H.

Abstract

AbstractThe ongoing pandemic caused by SARS-CoV-2 has gone through various phases. From the initial outbreak the virus has mutated several times, with some lineages showing even stronger infectivity and faster spread than the original virus. Among all the variants, beta, gamma, delta and the latest (omicron) are currently classified as variants of concern (VOC) while the remaining are labelled either as variants of interest (VOI) or variants under monitoring (VUM). In this work, we have focused on the mutations observed in important variants, particularly at the receptor-binding domain (RBD) of the spike protein that is responsible for the interactions with the host ACE2 receptor and binding of antibodies. Studying these mutations is particularly important for understanding the viral infectivity, spread of the disease and for tracking the escape routes of this virus from antibodies. Molecular dynamics (MD) based alchemical free energy calculations have been shown to be very accurate in predicting the free energy change due to a mutation that could have a deleterious or a stabilising effect on the protein itself or its binding affinity to another protein. Here, we investigated the significance of six commonly observed spike RBD mutations on the stability of the spike protein binding to ACE2 by free energy calculations using high throughput MD simulations. For comparison, we also used other (rigorous and non-rigorous) binding free energy prediction methods and compared our results with the experimental data if available. The alchemical free energy-based method consistently predicted the free-energy changes with an accuracy close to ±1.0 kcal/mol when compared with the available experimental values. As per our simulation data the most significant mutations responsible for stabilising the spike RBD interactions with human ACE2 are N501Y and L452R.

Publisher

Cold Spring Harbor Laboratory

Cited by 2 articles. 订阅此论文施引文献 订阅此论文施引文献,注册后可以免费订阅5篇论文的施引文献,订阅后可以查看论文全部施引文献

同舟云学术

1.学者识别学者识别

2.学术分析学术分析

3.人才评估人才评估

"同舟云学术"是以全球学者为主线,采集、加工和组织学术论文而形成的新型学术文献查询和分析系统,可以对全球学者进行文献检索和人才价值评估。用户可以通过关注某些学科领域的顶尖人物而持续追踪该领域的学科进展和研究前沿。经过近期的数据扩容,当前同舟云学术共收录了国内外主流学术期刊6万余种,收集的期刊论文及会议论文总量共计约1.5亿篇,并以每天添加12000余篇中外论文的速度递增。我们也可以为用户提供个性化、定制化的学者数据。欢迎来电咨询!咨询电话:010-8811{复制后删除}0370

www.globalauthorid.com

TOP

Copyright © 2019-2024 北京同舟云网络信息技术有限公司
京公网安备11010802033243号  京ICP备18003416号-3