Computational study of p\(\varvec{K}_\text{a}\) shift of aspartate residue in thioredoxin: role of conformational sampling

Alchemical free energy calculations are widely used in predicting p\(K_\text{a}\), 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 p\(K_\text{a}\) of the buried Asp\(_{26}\) residue in thioredoxin protein. We discuss the importance of enhanced sampling in the p\(K_\text{a}\) calculations.

Graphical abstract

By using a computational technique that enhances the conformational sampling and alchemical transformation, we predict the pKa shift of the buried Asp26 residue in thioredoxin protein.