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Abstract
Protein stability and function relies on residues being in their appropriate ionization
states at physiological pH. In situ residue pK(a)s also provides a sensitive measure
of the local protein environment. Multiconformation continuum electrostatics (MCCE)
combines continuum electrostatics and molecular mechanics force fields in Monte Carlo
sampling to simultaneously calculate side chain ionization and conformation. The response
of protein to charges is incorporated both in the protein dielectric constant (epsilon(prot))
of four and by explicit conformational changes. The pK(a) of 166 residues in 12 proteins
was determined. The root mean square error is 0.83 pH units, and >90% have errors
of <1 pH units whereas only 3% have errors >2 pH units. Similar results are found
with crystal and solution structures, showing that the method's explicit conformational
sampling reduces sensitivity to the initial structure. The outcome also changes little
with protein dielectric constant (epsilon(prot) 4-20). Multiconformation continuum
electrostatics titrations show coupling of conformational flexibility and changes
in ionization state. Examples are provided where ionizable side chain position (protein
G), Asn orientation (lysozyme), His tautomer distribution (RNase A), and phosphate
ion binding (RNase A and H) change with pH. Disallowing these motions changes the
calculated pK(a).