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. In this work we will use non-linear dimensionality reduction techniques, in particular the Scalable Isomap (SciMap) approach, and molecular dynamics (MD) simulations on multiple protein structures to efficiently characterize the free energy landscape and the thermodynamics of the complexes formed by the Human Complement Component C3d and its inhibitor, the S. Auerus extra-cellular fibrinogen binding protein (Efb-C) and its mutants, R131A and N138A. The continuation of computational effort, initiated by the current DAC allocation, will consist of two main stages: 1. Enrichment of the conformational space spanned by the equilibrium ensemble by performing parallel MD simulations employing the AMBER software. 2. Characterization of the low energy landscapes of the obtained complexes by describing them by means of a small number of collective reaction coordinates via a non-linear parallel dimensionality reduction algorithm implemented through the SciMap code developed by our research group. As a result of this work we expect to obtain a detailed description of the low energy landscapes of the above mentioned bound complexes.
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