Computational Study of pKa shift of Aspartate residue in Thioredoxin: Role of Configurational Sampling and Solvent Model

TL;DR

This study investigates how enhanced conformational sampling and solvent models influence the accuracy of pKa predictions for Aspartate in thioredoxin using alchemical free energy methods.

Contribution

It introduces a temperature-accelerated sampling technique for pKa calculations and evaluates solvent model effects, improving prediction reliability.

Findings

Enhanced sampling improves pKa prediction accuracy.

Solvent model choice significantly affects pKa values.

Temperature acceleration aids in capturing relevant conformations.

Abstract

Alchemical free energy calculations are widely used in predicting pKa, and binding free energy calculations in biomolecular systems. These calculations are carried out using either Free Energy Perturbation (FEP) or Thermodynamic Integration (TI). Numerous efforts have been made to improve the accuracy and efficiency of such calculations, especially by boosting conformational sampling. In this paper, we use a technique that enhances the conformational sampling by temperature acceleration of collective variables for alchemical transformations and applies it to the prediction of pKa of the buried Asp 26 residue in thioredoxin protein. We discuss the importance of enhanced sampling in the pKa calculations. The effect of the solvent models in the computed pKa values is also presented.