Multi-conformation continuum electrostatics An efficient, accurate program for calculation of pKas and Ems in proteins

Mao, J.; Song, Y.; Gunner, M.

The protonation of amino acids, substrates and ligands and oxidation states of redox active cofactors are of central importance for protein folding, stability, and function. The complexity of the protein's response to changes in charge makes it hard to calculate the thermodynamics of ionization state changes within proteins. Thus, changes in protein and solvent structure occur to stabilize different ionization states producing a location specific response. Multi-conformation continuum electrostatics (MCCE) is a hybrid method which combines continuum electrostatics and molecular mechanics. It uses Monte Carlo sampling to calculate equilibrium distributions of ionization states and positions of side chains and ligands. Poisson-Boltzmann, continuum electrostatics interactions are determined with DelPhi. Torsion and Lennard-Jones energies are included for side chain rotamers and ligand positions. Thus, MCCE differs from standard continuum electrostatics calculations by treating side chain motions in response to charge changes explicitly while retaining a continuum view of the solvent. Major improvements in the program will be reported, including the ability to consider repacking in the protein interior with full rotomer search as a function of pH. The new version is implemented on Linux, IRIX, and Mac OSX and provides AMBER or CHARMM parameters for the non-electrostatic interactions. Examples of the use of MCCE for calculating functionally significant pKs and Ems in bacteriorhodopsin, bacterial reaction centers and cytochromes, and exploring transmembrane proton conduction channels will be presented.