NDLI: A novel ensemble-based scoring and search algorithm for protein redesign, and its application to modify the substrate specificity of the gramicidin synthetase A phenylalanine adenylation enzyme

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A novel ensemble-based scoring and search algorithm for protein redesign, and its application to modify the substrate specificity of the gramicidin synthetase A phenylalanine adenylation enzyme

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A novel ensemble-based scoring and search algorithm for protein redesign, and its application to modify the substrate specificity of the gramicidin synthetase A phenylalanine adenylation enzyme

Content Provider	ACM Digital Library
Author	Stevens, Brian W. Donald, Bruce R. Lilien, Ryan H. Anderson, Amy C.
Abstract	Realization of novel molecular function requires the ability to alter molecular complex formation. Enzymatic function can be altered by changing enzyme-substrate interactions via modification of an enzyme's active site. A redesigned enzyme may either perform a novel reaction on its native substrates or its native reaction on novel substrates. A number of computational approaches have been developed to address the combinatorial nature of the protein redesign problem. These approaches typically search for the global minimum energy conformation among an exponential number of protein conformations. We present a novel algorithm for protein redesign, which combines a statistical mechanics-derived ensemble-based approach to computing the binding constant with the speed and completeness of a branch-and-bound pruning algorithm. In addition, we developed an efficient deterministic approximation algorithm, capable of approximating our scoring function to arbitrary precision. In practice, the approximation algorithm decreases the execution time of the mutation search by a factor of ten. To test our method, we examined the Phe-specific adenylation domain of the non-ribosomal peptide synthetase gramicidin synthetase A (GrsA-PheA). Ensemble scoring, using a rotameric approximation to the partition functions of the bound and unbound states for GrsA-PheA, is first used to predict binding of the wildtype protein and a previously described mutant (selective for leucine), and second, to switch the enzyme specificity toward leucine, using two novel active site sequences computationally predicted by searching through the space of possible active site mutations. The top scoring in silico mutants were created in the wetlab and dissociation / binding constants were determined by fluorescence quenching. These tested mutations exhibit the desired change in specificity from Phe to Leu. Our ensemble-based algorithm which flexibly models both protein and ligand using rotamer-based partition functions, has application in enzyme redesign, the prediction of protein-ligand binding, and computer-aided drug design.
Starting Page	46
Ending Page	57
Page Count	12
File Format	PDF
ISBN	1581137559
DOI	10.1145/974614.974622
Language	English
Publisher	Association for Computing Machinery (ACM)
Publisher Date	2004-03-27
Publisher Place	New York
Access Restriction	Subscribed
Subject Keyword	Molecular ensemble Protein-ligand binding Protein design Protein flexibility Enzyme design Fluorescence binding assay Non-ribosomal peptide synthetase
Content Type	Text
Resource Type	Article

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