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J Am Chem Soc. 2018 Feb 7;140(5):1639-1648. doi: 10.1021/jacs.7b08569. Epub 2018 Jan 27.

A Coupled Ionization-Conformational Equilibrium Is Required To Understand the Properties of Ionizable Residues in the Hydrophobic Interior of Staphylococcal Nuclease.

Author information

1
School of Chemistry and Molecular Engineering, Shanghai Engineering Research Center of Molecular Therapeutics and New Drug Development, East China Normal University , Shanghai, 200062, China.
2
Department of Chemistry, University of Florida , Gainesville, Florida 32611, United States.
3
Department of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University , Nanjing, 210009, China.
4
Department of Chemistry and Chemical Biology and BioMaPS Institute, Rutgers University , Piscataway, New Jersey 08854, United States.
5
NYU-ECNU Center for Computational Chemistry at NYU Shanghai , Shanghai, 200062, China.

Abstract

Ionizable residues in the interior of proteins play essential roles, especially in biological energy transduction, but are relatively rare and seem incompatible with the complex and polar environment. We perform a comprehensive study of the internal ionizable residues on 21 variants of staphylococcal nuclease with internal Lys, Glu, or Asp residues. Using pH replica exchange molecular dynamics simulations, we find that, in most cases, the pKa values of these internal ionizable residues are shifted significantly from their values in solution. Our calculated results are in excellent agreement with the experimental observations of the Garcia-Moreno group. We show that the interpretation of the experimental pKa values requires the study of not only protonation changes but also conformational changes. The coupling between the protonation and conformational equilibria suggests a mechanism for efficient pH-sensing and regulation in proteins. This study provides new physical insights into how internal ionizable residues behave in the hydrophobic interior of proteins.

PMID:
29308643
DOI:
10.1021/jacs.7b08569
[Indexed for MEDLINE]

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