Simulation method for calculating the entropy and free energy of peptides and proteins

A method called complete hypothetical scanning Monte Carlo has been introduced for calculating the absolute entropy, S, and free energy, F, of fluids. Here, the method is extended to peptide chains in vacuum. Thus, S is calculated from a given sample by reconstructing each conformation step-by-step by using transition probabilities (TPs); at each step, part of the chain coordinates have already been determined (the "frozen past"), and the TP is obtained from a Monte Carlo simulation of the (future) part of the chain whose TPs as yet have not been calculated. Very accurate results for S and F are obtained for the helix, extended, and hairpin microstates of a simplified model of decaglycine (Gly)(10) and (Gly)(16). These results agree well with results obtained by the quasiharmonic approximation and the local states method. The complete HSMC method can be applied to a macromolecule with any degree of flexibility, ranging from local fluctuations to a random coil. Also, the difference in stability, Delta F(mn) = F(m) - F(n) between significantly different microstates m and n can be obtained from two simulations only without the need to resort to thermodynamic integration. Our long-term goal is to extend this method to any peptide and apply it to a peptide immersed in a box with explicit water.