Machine learning in molecular biophysics: Protein allostery, multi-level free energy simulations, and lipid phase transitions

Machine learning (ML) techniques have been making major impacts on all areas of science and engineering, including biophysics. In this review, we discuss several applications of ML to biophysical problems based on our recent research. The topics include the use of ML techniques to identify hotspot residues in allosteric proteins using deep mutational scanning data and to analyze how mutations of these hotspots perturb co-operativity in the framework of a statistical thermodynamic model, to improve the accuracy of free energy simulations by integrating data from different levels of potential energy functions, and to determine the phase transition temperature of lipid membranes. Through these examples, we illustrate the unique value of ML in extracting patterns or parameters from complex data sets, as well as the remaining limitations. By implementing the ML approaches in the context of physically motivated models or computational frameworks, we are able to gain a deeper mechanistic understanding or better convergence in numerical simulations. We conclude by briefly discussing how the introduced models can be further expanded to tackle more complex problems.