Elucidating the Conformational Dependence of Calculated pKa Values.

Area of Science:

• Computational Biology
• Biophysical Chemistry
• Protein Science

Background:

• Protein residue ionization states are crucial for function.
• Calculating pKa values is essential for understanding protein behavior.
• Poisson-Boltzmann continuum theory is a common method for pKa calculations.

Purpose of the Study:

• Investigate the variability of calculated protein residue pKa values.
• Analyze the relationship between pKa fluctuations and conformational changes.
• Understand how protein microenvironments influence pKa variability.

Main Methods:

• Utilized Poisson-Boltzmann continuum theory for pKa calculations.
• Assessed pKa variability in response to small conformational fluctuations.
• Analyzed electrostatic microenvironments of protein core and surface sites.

Main Results:

• Protein core sites exhibit larger pKa fluctuations with less conformational variability.
• Surface sites show smaller pKa fluctuations with greater conformational variability.
• Atypical surface sites at charge potential interfaces display significant pKa fluctuations.

Conclusions:

• Protein core and surface sites have fundamentally different pKa fluctuation behaviors.
• Electrostatic microenvironment heterogeneity dictates pKa variability.
• Conformational flexibility and pKa stability are inversely related for most sites.