Application of the primary hydration shell approach to locally enhanced sampling simulated annealing: computer simulation of thyrotropin-releasing hormone in water

A unified model of simulated annealing with locally enhanced sampling (LES) in a primary hydration shell (PHS) aqueous environment is developed and tested by predicting the structure of the tripeptide thyrotropin-releasing hormone (TRH) in solution. The model extends the formulation of the restraining force in the PHS method as a function of temperature, number of copies in the LES method, and shell thickness. The dependence of the restraining force on temperature can be shown to follow the relationship c(1)T - c(2), which can be derived from the expression for kinetic energy in molecular dynamics simulations. The calibration of the restraining force for different simulation conditions reveals the dependence of c(1) and c(2) on the number of copies in the LES method and the thickness of the PHS. The predicted structure of TRH is in very good agreement with results from NMR experiments and from a 10-ns PHS simulation at 300 K. The method promises to be useful in predicting structure of peptides and proteins in an aqueous environment.