Molecular modeling and dynamics of biologically active peptides: application to neuropeptide Y.

A methodology is presented to allow results from molecular dynamics simulations to be combined with pharmacological binding and activity measurements in order to study the structure-function relationships of neuropeptide Y. This approach is a general one and should also be applicable to other peptides for which stable structures are known to exist in solution. The basis of the method is the calculation of energetically stable structures via a simulate and test approach. This approach uses molecular dynamics simulations to search conformational space in order to find low potential energy structures. The energetic stability of the structures is then tested via additional simulations. Once energetic stability has been achieved, perturbations of the structure may be performed via molecular modeling. The simulate and test approach is then used to obtain energetically stable structures for the perturbed compound. Comparison between the energetically stable starting and perturbed structures can then be made concerning both structural and dynamic changes. By using an energetically stable structure prior to the perturbation, the assumption can be made that the calculated differences are primarily due to the perturbation rather than to one or both of the structures reaching a more energetically favorable state. It should be emphasized that the calculations are being performed employing a limited physical model such that the influence of that model on the observed results must always be taken into account.