Calculation of the entropy and free energy of peptides by molecular dynamics simulations using the hypothetical...

Hypothetical scanning (HS) is a method for calculating the absolute entropy S and free energy F from a sample generated by any simulation technique. With this approach each sample configuration is reconstructed with the help of transition probabilities (TPs) and their product leads to the configuration's probability, hence to the entropy. Recently a new way for calculating the TPs by Monte Carlo (MC) simulations has been suggested, where all system interactions are taken into account. Therefore, this method--called HSMC--is in principle exact where the only approximation is due to insufficient sampling. HSMC has been applied very successfully to liquid argon, TIP3P water, self-avoiding walks on a lattice, and peptides. Because molecular dynamics (MD) is considered to be significantly more efficient than MC for a compact polymer chain, in this paper HSMC is extended to MD simulations as applied to peptides. Like before, we study decaglycine in vacuum but for the first time also a peptide with side chains, (Val)(2)(Gly)(6)(Val)(2). The transition from MC to MD requires implementing essential changes in the reconstruction process of HSMD. Results are calculated for three microstates, helix, extended, and hairpin. HSMD leads to very stable differences in entropy TDeltaS between these microstates with small errors of 0.1-0.2 kcal/mol (T=100 K) for a wide range of calculation parameters with extremely high efficiency. Various aspects of HSMD and plans for future work are discussed.