Computational study of p K_a shift of aspartate residue in thioredoxin: role of conformational sampling

lchemical free energy calculations are widely used in predicting p K_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_a of the buried Asp _26 residue in thioredoxin protein. We discuss the importance of enhanced sampling in the p K_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.