TITLE:

COMPUTATIONAL APPROACHES TO PROTEIN (AND ENZYME) DESIGN (No. 39)

DATE:

Friday, February 20th, 2004

TIME:

3:30 PM

LOCATION:

GMCS 214

SPEAKER:

John Love, Department of Chemistry, San Diego State University

ABSTRACT:

A main aim of our research program is to combine the principles of supramolecular chemistry with the emerging tools of protein engineering. The goal is to increase our understanding of the underlying physical principles of molecular self-assembly and thus enable us to design the building blocks and raw material for the emerging field of biological material science. The first step in driving de novo self-assembly is the computational docking of the proteins together in the predefined orientation. To this end we have modified an established docking algorithm, the geometric recognition algorithm (GRA). The GRA treats the molecules as rigid bodies and rigorously assesses interfacial surface complementarity as a function of translational and rotational position. This process is computationally intensive yet has been rendered tractable by utilizing the Fourier Correlation Theorem. Upon obtaining the optimal intermolecular atomic coordinates the two molecules are treated as one and a suite of highly developed protein design algorithms, which utilize advanced molecular mechanics force fields, is used to computationally repack the interfacial side-chains in a manner analogous to the cores of well folded proteins. The protein design algorithms are contained in the ORBIT (Optimal Rotomers Based on Iterative Techniques) suite of algorithms. The primary function of ORBIT is to return a mutated protein sequence optimized for a given three-dimensional backbone structure. This side-chain selection process is computationally intensive and can result in amino acid rotomer libraries with complexities on the order of 1 x 10200. It is not possible to sum and compare the energies of all possible sets of rotomers in this complexity range. Therefore the optimal amino acid sequence contained in the final global minimum energy conformation is selected from the large rotomer library upon application of the Dead End Elimination algorithm.

I will describe the above algorithms as well as recent examples of the successful application of our docking and design methods. In addition I will describe how we are utilizing the above methods to design a novel variant of the protein myoglobin engineered to catalyze an important reaction ? the hydrolysis of organophosphates typified by pesticides and nerve agents.

HOST:

Andrew Cooksy

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