APPLICATION OF GLYCAM IN GENERATION OF SOLVATED POTENTIAL ENERGY SURFACES

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This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. The construction of a Ramachandran plot about two torsional bonds, for prediction of the most preferred conformation of biological molecules, is usually carried out typically in vacuo -- using the potential energy based on a molecular mechanics or quantum mechanical calculations. However, it has become clear over the past few years that water can play an integral part in determining the most stable structure of macromolecules, including carbohydrates. Furthermore, in carbohydrates, an energy minimization will neglect the number of possible conformations due to the large number of rotatable bonds from the hydroxyl moieties on the sugar rings. Also, entropic effects which might play an important role in the energy barrier for inter-conversion between various states, are completely neglected. The construction of a free-energy profile using fully solvated MD simulations could remedy these shortcomings. The determination of the free energy or potential of mean force, using umbrella sampling, has been extensively used in the past for studying the conformations of peptides, but has scarcely been used for carbohydrates (a search in the literature only points to two studies since 1995). While useful information has already been extracted from these studies -- such as the fact that the global minimum from the potential energy surface can be quite different from that predicted from the potential of mean force simulation -- no comparison to experiment has ever been done, providing little information about the performance of the force fields that have been used. We propose to carry out a two-dimensional potential of mean force calculations about the F/Y interglycosidic torsional angles of maltose, which has been extensively studied both theoretically and experimentally. This simulation will be carried out in solution, with several thousand water molecules included, using particle-mesh Ewald to treat long-range electrostatics and will make use of the latest Glycam forcefield, which is part of the AMBER package. The Glycam forcefield has been tailored to accurately describe the structure and dynamics of carbohydrates in solution. MD simulations will be carried out at 10 degree increments over the F/Y interglycosidic linkages using a harmonic biasing potential with a 5 kcal/mol*rad2 force constant. The simulation will then be unbiased using the weighted histogram analysis method (WHAM), which has been shown to be a robust and stable method even for multidimensional surfaces. This will provide us a unique opportunity to compare the results of the potential of mean force simulation with the experimentally predicted structure of maltose. It will also be possible to assess the performance of the Glycam forcefield in structure predictions, and provide useful information about the role of water in the preferred structure of maltose.