Conformational Sampling

    In many of our molecular modeling investigations the goal is to determine the lowest-energy conformation of a molecule. The larger the molecule is, the more difficult this becomes. The schematic potential energy surface at right illustrates the concept. Large molecules have a large number of possible conformations, many of which represent local minima on the potential energy surface. The goal of the calculation is to find low-energy minima including the global minimum. The first step in a MM calculation is to obtain an initial molecular structure. Starting structures are often built on the computer using the AMBER software or another modeling program called HyperChem. For large molecules it is useful to start with a known structure obtained by some other method, such as X-ray crystallography. These structures can often be obtained from the Protein Data Bank, a collection of 3-D biological molecular structure data. If the procedure used to sample the molecule's conformational space is adequate, the results of the MM calculation should not depend on the choice of starting structure. After obtaining an initial structure, the next step is to optimize its geometry by minimizing its energy. The resulting conformation corresponds to a local minimum on the potential energy surface.
    Most often we are interested in the global minimum and/or the lowest-energy local minima. To find those stable conformations, we use a technique called simulated annealing. In this procedure we increase the internal energy of the molecule and allow the starting structure to change accordingly. By reminimizing the energy of the resulting structure, a new stable conformation can be found. By repeating this procedure the global minimum (lowest-energy) structure can ultimately be found. The details of this sampling process can vary.
    Sometimes it is also useful to examine the change of shape as a consequence of thermal motion for comparison with experiment, which is typically carried out at room temperature. In these instances molecular dynamics calculations are done to sample conformation space at a specific temperature.
    For investigations of large molecules (such as the Aβ peptides) conducted in collaboration with the Shea Group, we use the replica exchange technique in order to sample conformational space efficiently at a given temperature. This technique takes both energetic and entropic effects into account.