Free Energy Calculations for Peptidesvia Deterministic Global

The BB algorithm is a deterministically based global optimization method that has been successfully used to locate the global minimum energy conformations of peptide systems. The goal of this procedure is to identify the native conformation of a given peptide by identifying the structure possessing the global minimum potential energy. However, a rigorous conformational search should locate the structure exhibiting the global minimum free energy. In this work, novel methods are developed for locating free energy global minimum conformations and clusters of peptides. These methods are based on an harmonic approximation for entropic eeects, which requires the ability to generate a dense ensemble of distinct low energy local minima. Two approaches, both based on the general concepts of the BB branch and bound framework, are used to generate these ensembles. In performing these calculations, potential energy contributions were modeled using an all-atom force eld. In addition, hydration eeects were also considered by utilizing a solvent{accessible volume of hydration shell model. The free energy analysis was applied to both the unsolvated and solvated forms of met{ and leu{enkephalin. It was found that both methods produce dense, Boltzmann-like, distributions of low energy metastable states. The inclusion of entropic effects was also found to innuence the prediction of free energy global minima. In addition, a 1 statistical treatment of the thermodynamics of folding showed that the transition temperature , which signiied a collapse from high energy, extended structures to a ground-state-like ensemble, could be identiied.