A method for efficient calculation of thermal stability of proteins upon point mutations

Bo Wang; Yifei Qi; Ya Gao; John Z H Zhang

doi:10.1039/d0cp00835d

A method for efficient calculation of thermal stability of proteins upon point mutations

Phys Chem Chem Phys. 2020 Apr 29;22(16):8461-8466. doi: 10.1039/d0cp00835d.

Authors

Bo Wang¹, Yifei Qi², Ya Gao³, John Z H Zhang⁴

Affiliations

¹ Shanghai Engineering Research Center of Molecular Therapeutics & New Drug Development, Shanghai Key Laboratory of Green Chemistry & Chemical Process, School of Chemistry and Molecular Engineering, East China Normal University, Shanghai 200062, China.
² Shanghai Engineering Research Center of Molecular Therapeutics & New Drug Development, Shanghai Key Laboratory of Green Chemistry & Chemical Process, School of Chemistry and Molecular Engineering, East China Normal University, Shanghai 200062, China and NYU-ECNU Center for Computational Chemistry at NYU Shanghai, Shanghai 200062, China. john.zhang@nyu.edu.
³ Shanghai Engineering Research Center of Molecular Therapeutics & New Drug Development, Shanghai Key Laboratory of Green Chemistry & Chemical Process, School of Chemistry and Molecular Engineering, East China Normal University, Shanghai 200062, China and School of Mathematics, Physics and Statistics, Shanghai University of Engineering Science, Shanghai 201620, China.
⁴ Shanghai Engineering Research Center of Molecular Therapeutics & New Drug Development, Shanghai Key Laboratory of Green Chemistry & Chemical Process, School of Chemistry and Molecular Engineering, East China Normal University, Shanghai 200062, China and NYU-ECNU Center for Computational Chemistry at NYU Shanghai, Shanghai 200062, China. john.zhang@nyu.edu and Department of Chemistry, New York University, NY, NY 10003, USA and Collaborative Innovation Center of Extreme Optics, Shanxi University, Taiyuan, Shanxi 030006, China.

PMID: 32281996
DOI: 10.1039/d0cp00835d

Abstract

A method for efficient prediction of the relative stability of a protein due to a single amino acid point mutation is presented. In this approach, we calculate the free energy change due to an arbitrary point mutation of a protein from a single MD trajectory of the wild type protein. The method is tested on 27 diverse protein systems with a total of 853 mutations and the calculated relative free energies show a generally good correlation with the experimental values (a correlation coefficient of 0.63). Comparison with the free energy perturbation (FEP) method and the recently developed machine learning methods on two different benchmark data sets shows that the current method is computationally efficient and also numerically reliable for predicting the changes in thermostability upon an arbitrary point mutation of a protein. A discussion is provided on how to further improve the accuracy of the method for the prediction of thermostability of proteins.

MeSH terms

Chemistry Techniques, Analytical / methods*
Computational Chemistry*
Point Mutation*
Protein Stability*
Proteins / genetics*
Temperature

Substances

Proteins