Determination of the reaction free energy profile using QM(DFTB)/MM and Multiple steered molecular dynamics (MSMD) strategy.

To determine the free energy of the reaction we used the MSMD method [56,57] which allows to link non equilibrium pulling trajectories with equilibrium properties like the free energy, and has been extensively used in our group to determine free energy profiles[57—60].

AG(>L) and W(>L) are the change in free energy and the external work performed on the system as it evolves from k 2 k0 to k, respectively.

Secondly, we analyzed the “forbidden” conformation and finally, we determined the free energy profile of the sulfenic acid to cyclic sulfenyl amide reaction using QM/MM methods in human PTPlB.

We initially analyzed the free energy difference between the forbidden-psi conformation and allowed helix conformation.

3B allows an estimation of how much energy proteins must pay to constraint the Cys in the reactive (forbidden-psi) conformation using the Ramachandran plot derived free energy , estimated it around 5.5 kcal/mol.

Importantly, the algorithm also provides the free energy P, which is an approximation to the model evidence.

This free energy approach yields better model scores than does the Akaike Information Criterion (AIC) or Bayesian Information Criterion (BIC) [95].

The optimal set of parameters, i.e., that obtained from the initialization that resulted in the maximal free energy , is reported in this manuscript.