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Structural and Chemical Biology @ Vanderbilt University |
Design of small molecule – protein interfaces
Members: Kristian Kaufmann , Eric Dawson
all research projects
Interactions of small molecules with proteins drive many biological processes. As such, designing protein-small molecule interfaces represents an attractive engineering goal. Possibilities include diverse applications from enzyme and drug design to use in molecular machines and antibiotics. In general, engineering proteins for specified function on small molecules follows the steps below.
1. Select protein topology
2. Identify a binding site within the selected topology
3. Search translational, rotational, conformational, and sequence degrees of freedom in the protein small molecule complex for the global minimum
4. Verify global minimum describes state satisfying design specifications.
The above steps involve aspects of both protein design and small molecule docking. My work with Rosetta focus on improving the current tools through implementing and fine tuning protocols integrating small molecule protein interfaces in Rosetta. Rosetta currently scores small molecule protein interactions. It can perform both protein small molecule interface design and small molecule docking in proteins. One of the major deficiencies in current code is restriction of small molecules to rigid conformations. I am implementing protocols the sample small molecule conformational space inside the Rosetta in an integrated fashion with the protein design algorithms present in Rosetta.
These changes fall under point three above. The degrees of freedom I am introducing into the design algorithm include the global translation and rotation of the small molecule in relation to the protein and the internal degrees of freedom encoded in the bond length, angles, and dihedrals. In order to reduce the search space I bias my search of the small molecule conformational space to relevant conformations through a scoring function derived from the Cambridge Structural Database. The pre-computed conformations can then be used as rotamers in a search of the small molecule protein interface.
Members: Kristian Kaufmann , Eric Dawson
all research projects
Interactions of small molecules with proteins drive many biological processes. As such, designing protein-small molecule interfaces represents an attractive engineering goal. Possibilities include diverse applications from enzyme and drug design to use in molecular machines and antibiotics. In general, engineering proteins for specified function on small molecules follows the steps below.
1. Select protein topology
2. Identify a binding site within the selected topology
3. Search translational, rotational, conformational, and sequence degrees of freedom in the protein small molecule complex for the global minimum
4. Verify global minimum describes state satisfying design specifications.
The above steps involve aspects of both protein design and small molecule docking. My work with Rosetta focus on improving the current tools through implementing and fine tuning protocols integrating small molecule protein interfaces in Rosetta. Rosetta currently scores small molecule protein interactions. It can perform both protein small molecule interface design and small molecule docking in proteins. One of the major deficiencies in current code is restriction of small molecules to rigid conformations. I am implementing protocols the sample small molecule conformational space inside the Rosetta in an integrated fashion with the protein design algorithms present in Rosetta.
These changes fall under point three above. The degrees of freedom I am introducing into the design algorithm include the global translation and rotation of the small molecule in relation to the protein and the internal degrees of freedom encoded in the bond length, angles, and dihedrals. In order to reduce the search space I bias my search of the small molecule conformational space to relevant conformations through a scoring function derived from the Cambridge Structural Database. The pre-computed conformations can then be used as rotamers in a search of the small molecule protein interface.