Interfacial water molecules contribute to antibody binding to the receptor-binding domain of SARS-CoV-2 spike protein

Abstract

Antibodies that recognize the spike protein of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), especially the neutralizing antibodies, carry great hope in the treatment and final elimination of COVID-19. Driven by a synchronized global effort, thousands of antibodies against the spike protein have been identified during the past two years, with the structural information available at atomistic detail for hundreds of these antibodies. We developed an improved molecular mechanics/Poisson–Boltzmann surface area (MM/PBSA) method including explicitly treated interfacial water to calculate the binding free energy between representative antibodies and the receptor binding domain (RBD) domain of SARS-COV-2 spike proteins. We discovered that explicit treatment of water molecules located at the interface between RBD and antibody effectively improves the results for the WT and variants of concern (VOC) systems. Interfacial water molecules, together with surface and internal water molecules, behave drastically from bulk water and exert peculiar impacts on protein dynamics and energy, and thus warrant explicit treatment to complement implicit solvent models. Our results illustrate the importance of including interfacial water molecules to approach efficient and reliable prediction of binding free energy.

Communicated by Ramaswamy H. Sarma

Keywords:

• SARS-CoV-2
• Binding free energy
• MM/PBSA
• interfacial water
• explicit water

Author contributions

LZ and QL designed the experiments, participated in the data analysis and writing of the manuscript. XZ and RW developed the related algorithm, performed the experiments and data analysis, and contributed to the writing of the manuscript.

Acknowledgments

We are grateful for the support and input to this project from other lab members.

Disclosure statement

No potential conflict of interest was reported by the authors.

Data and code available

The settings of the MD simulation and all related source coded can be downloaded from https://github.com/MeetXinZhang/HyHOH.

Additional information

Funding

L. Zhou is supported by fundings from the National Natural Science Foundation of China (#32171150) and Shenzhen Bay Laboratory (#S211101001-3).