The virtual mixture of multiple states (VMMS) method is a new approach to study Chemical equilibrium of multiple states.    This method constructs a virtual mixture of multiple states (VMMS) to sample the conformational space of all chemical states simultaneously.  Transition between states is implicated by the change of their molar fraction to avoid any energy barrier related to state transition, such as solvent reorientation in explicit solvent simulation.  Simulation of a VMMS system allows efficient calculation of relative free energies of all states, which in turn determine their equilibrium molar fractions. For systems with a large number of state transition sites, an implicit site approximation is introduced to minimize the cost of simulation. Application of the VMMS method to the SNase variants, we obtained pKa values of ionizable residues inside SNase and investigated the physics underlining the pKa shifts.  Our calculation results agree well with experimental measurement, validate the VMMS method for pKa calculation and provide insight into the origin of pKa shifts for buried residues inside a protein.

Origin of pKa shifts of SNase internal ionizable residues via VMMS simulation in explicit water

251st National Meeting (2016)

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