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Co-PI: Shekhar Garde

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Molecular Simulation-Based Descriptors

Co-Investigator: Shekhar Garde

Assistant Professor, Chemical and Biological Engineering, Rensselaer Polytechnic Institute

Molecular dynamics simulations of individual proteins in aqueous solutions will be carried out to develop new descriptors that include specific molecular level details of the protein / water interface. These simulations allow us to better characterize the physico-chemical nature of the protein surface that explicitly includes information about surface hydration. Specifically, two new directions will be pursued to this end.

Figure 7. Left panel: Densities of hydrophobic probe molecules (red spheres) and water molecules (blue spheres) near protein surface obtained from MD simulation of protein Subtilisin BPN’. Right panel: water densities near the active site region of the protein. These three-dimensional density maps can be used to develop water structure-based and probe molecule binding affinity-based descriptors.

Water structure based descriptors: Several thousand detailed snapshots of protein water systems will be collected from a molecular dynamics simulation of a protein in a bath of solvent molecules. A grid will be placed in the region surrounding the protein and local density of water molecules at the location of grid points will be calculated. Preliminary studies show that the local density of water varies from small values to as high as 5-10 times the bulk density of water, depending on the nature of amino acid in the given surface region of the protein. Three-dimensional density data obtained in this fashion provides a molecularly detailed characterization of the hydration of different regions on the protein surface. These density values will be used to develop new water-structure based descriptors for QSPR calculations. The non-uniformity of hydration of different parts of the protein surfaces can be easily captured by such descriptors (Figure 7).

Probe Molecule Binding Based Descriptors: The water structure based descriptors described above treat water as a ligand and characterize the binding of water to the protein surface. In fact, this idea can be generalized to include an array of other small molecules as probes to map heterogeneity of a protein surface. Such a set of probe molecules can include benzene, octane, ethanol, ion-exchange ligands, and several ions etc. We will perform simulations of a protein in aqueous solutions of probe molecules. Analysis of simulation trajectories can reveal binding preferences of probe molecules to various locations on the protein surface. Local densities of probe molecules near the protein surface can therefore be used to develop descriptors that better capture chemical heterogeneity of the protein surface.

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