Improved pKa calculations through flexibility based sampling of a water-dominated interaction scheme

Area of Science:

• Computational biochemistry and biophysics
• Protein structure and function analysis

Background:

• Ionizable groups are crucial for biological functions.
• Accurate computation of pK(a) values is challenging due to model approximations and conformational flexibility.
• Understanding hydration entropy changes upon charge burial is key for predicting protein behavior.

Purpose of the Study:

• To develop an improved empirical model for calculating pK(a) values of ionizable groups in proteins.
• To investigate hydration entropy changes upon charge burial.
• To enhance the accuracy of computational methods for predicting pH-dependent protein properties.

Main Methods:

• Comparison of calculated and experimental pK(a)s for inflexible active-site side chains.
• Development of an empirical model for hydration entropy changes.
• Application of finite difference (FD) and Debye-Hückel (DH) interaction schemes for ionizable residues.
• Estimation of conformational relaxation using side chain solvent accessibility.

Main Results:

• The new FD/DH method significantly improves pK(a) calculations for a mixed set of ionizable residues.
• The model accurately distinguishes between buried and solvent-accessible groups.
• Improved prediction of pH-dependence of electrostatic energy and identification of active sites by electrostatic strain.

Conclusions:

• The developed FD/DH computational framework offers a fast and accurate approach for pK(a) prediction.
• This method enhances understanding of electrostatic contributions to protein stability and function.
• It provides substantial improvements for structural genomics, particularly in active-site identification.