An optimized thermodynamics integration protocol for identifying beneficial mutations in antibody design

Frontiers in Immunology

Immunology

Zhiteng Li¹  Yicheng Guo¹  Zizhang Sheng¹  Maple Wang¹  David D. Ho¹  Jude S. Bimela² 

[1] Aaron Diamond AIDS Research Center, Columbia University Vagelos College of Physicians and Surgeons, New York, NY, United States;Zuckerman Mind Brain Behavior Institute, Columbia University, New York, NY, United States;

关键词: thermodynamics integration;    antibody design;    antibody 10-40;    SARS-CoV-2;    molecular dynamics simulation;   

DOI  :  10.3389/fimmu.2023.1190416

 received in 2023-03-20, accepted in 2023-04-28,  发布年份 2023

来源: Frontiers

【 摘 要 】

Accurate identification of beneficial mutations is central to antibody design. Many knowledge-based (KB) computational approaches have been developed to predict beneficial mutations, but their accuracy leaves room for improvement. Thermodynamic integration (TI) is an alchemical free energy algorithm that offers an alternative technique for identifying beneficial mutations, but its performance has not been evaluated. In this study, we developed an efficient TI protocol with high accuracy for predicting binding free energy changes of antibody mutations. The improved TI method outperforms KB methods at identifying both beneficial and deleterious mutations. We observed that KB methods have higher accuracies in predicting deleterious mutations than beneficial mutations. A pipeline using KB methods to efficiently exclude deleterious mutations and TI to accurately identify beneficial mutations was developed for high-throughput mutation scanning. The pipeline was applied to optimize the binding affinity of a broadly sarbecovirus neutralizing antibody 10-40 against the circulating severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) omicron variant. Three identified beneficial mutations show strong synergy and improve both binding affinity and neutralization potency of antibody 10-40. Molecular dynamics simulation revealed that the three mutations improve the binding affinity of antibody 10-40 through the stabilization of an altered binding mode with increased polar and hydrophobic interactions. Above all, this study presents an accurate and efficient TI-based approach for optimizing antibodies and other biomolecules.

【 授权许可】

Unknown   
Copyright © 2023 Sheng, Bimela, Wang, Li, Guo and Ho