Towards a free energy-based elastic network model and its application to the SARS-COV2 binding to ACE2.

Classical normal mode analysis (cNMA) is a standard method for studying the equilibrium vibrations of macromolecules. A major limitation of cNMA is that it requires a cumbersome step of energy minimization that also alters the input structure significantly. Variants of NMA exist that perform normal mode analysis directly on PDB structures without energy minimization, while maintaining most of the accuracy of cNMA. sbNMA is such a model. sbNMA uses an all-atom force field as cNMA does, which includes bonded terms such as bond stretching, bond angle bending, torsional, improper, and non-bonded terms such as van der Waals interactions. Electrostatics was not included in sbNMA because it introduced negative spring constants. In this work, we present a way to incorporate most of the electrostatic contributions in normal mode computations, which marks another significant step toward a free-energy-based elastic network model for normal mode analysis. The vast majority of elastic network models are entropy models. One significance of having a free energy-based model for normal mode analysis is that it allows one to study the contributions of both entropy and enthalpy. As an application, we apply this model to study the binding stability between SARS-COV and angiotensin converting enzyme 2 (or ACE2). Our results show that the stability at the binding interface is contributed nearly equally by hydrophobic interactions and hydrogen bonds.