Traditionally, the average protonation of each residue in the protein as a function of pH is obtained with programs using Monte Carlo (MC) sampling or cpH MD. The MCCE program uses MC sampling to generate a Boltzmann distribution of protonation and tautomer states, side chain rotamers and charged ligands. New functionality allows analysis of the millions of accepted microstates. Each microstate defines the protonation state of each acid and base in the simulation. The changes in microstate distributions provide greater insight into proton transport processes. Simulations can now extract the distribution of: (1) the total protein charge; (2) the distribution of protons amongst the protonatable residues in microstates with the same change (tautomer); (3) the correlation of protonation states in groups of residues; and (3) estimates of changes in enthalpy and entropy in different functional states. Examples from the proton pumps Complex I and cytochrome c oxidase will be described. Identifying high probability microstates can also provide improved input for MD simulations.

Analyzing the ensemble of protonation states for in a protein at equilibrium

ACS Spring 2022

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