Statistical Mechanical Design Principles for Coarse-Grained Interactions across Different Conformational Free Energy Surfaces.

Systematic bottom-up coarse-graining (CG) of molecular systems provides a means to explore different coupled length and time scales while treating the molecular-scale physics at a reduced level. However, the configuration dependence of CG interactions often results in CG models with limited applicability for exploring the parametrized configurations. We propose a statistical mechanical theory to design CG interactions across different configurations and conditions. In order to span wide ranges of conformational space, distinct classical CG free energy surfaces for characteristic configurations are identified using molecular collective variables. The coupling interaction between different CG free energy surfaces can then be systematically determined by analogy to quantum mechanical approaches describing coupled states. The present theory can accurately capture the underlying many-body potentials of mean force in the CG variables for various order parameters applied to liquids, interfaces, and in principle proteins, uncovering the complex nature underlying the coupling interaction and imparting a new protocol for the design of predictive multiscale models.