of Work:
Aims : The goal of this project is to improve the quality of molecular modeling and molecular dynamics simulations, and to apply these methods to highly pertinent problems, both from the view of biomedical relevance and methodological challenge. In principle, molecular dynamics simulations offer a detailed atomic level description of the interactions between key biomoilecules of significance to human health. In practice, this methodology is limited by the short simulation times (less than 100 nanoseconds) available with current computer technology, which translates into limited conformational sampling, and by the inaccuracies in the empirical force fields used in the simulations. While a number of groups are attempting to relieve the conformational sampling bottlenecks, we are focusing on improvements to the accuracy of representations, without sacrificing computational efficiency. The long range goal is to do simulations from """"""""first principles"""""""", i.e. without resorting to empirical fitting procedures. This fiscal year our major accomplishment was to extend our method of efficiently treating electrostatics to more detailed models of the electron density. Application to sulfotransferase enzymes. Generally, we wish to understand the similarities and differences between biological phosphates and sulfates. Specifically, we are focusing on providing molecular and quantum mechanical models that relate directly to the crystal structures emerging from our collaborator's laboratory. This fiscal year we completed the building of the ternary complex of heparan sulfotransferase, PAPS, and a heparan dimer. This model has then been used to complete several long simulations of the solvated model. The results of the simulation confirm the importance of key residues previously identified by crystallographic and mutagenesis studies, and suggest the involvement of water in the reaction.
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