Ionizable residues present in the hydrophobic interior of proteins, despite being rare, play major roles in important biological processes like energy transduction and enzyme catalysis. Internal ionizable residues in proteins have shifted apparent pKa values with respect their intrinsic pKa in bulk water. An atomistic understanding of the factors determining the anomalous pKa values is very important. In the present work, we study the diversity of the pH-dependent conformational changes undergone by mutants of Staphylococcal Nuclease (SNase), due to the presence of internal ionizable residues, using pH replica exchange molecular dynamics. We present thermodynamic models to find the ‘conformation-specific pKa values’ of the internal ionizable residues and explain their association with the observed ‘apparent pKa’. We extend our study to understand the pH-dependent structural and thermodynamic properties of ionizable residue pairs within the hydrophobic interior of SNase.

pH-Dependent properties of ionizable residues in the hydrophobic interior of a protein

2019 Spring National Meeting

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