Computational method for designing enzymes for incorporation of amino acid analogs into proteins

a technology design methods, applied in the field of amino acid analog design and protein incorporation, can solve the problems of limited mutagenesis to the 20 naturally occurring amino acids, inability to circumvent the specificity of synthetases, and modest chemical functionality that has been accessed by this method, and achieve the effect of facilitating the accommodation of amino acid analogs

Inactive Publication Date: 2006-08-10
CALIFORNIA INST OF TECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0007] The instant invention provides methods and computational tools for systematically modifying the substrate specificity of AminoAcyl tRNA Synthetases (AARSs) to enable them to utilize amino acid analogs in cell-fr

Problems solved by technology

Though this process has been very useful for designing new macromolecules with precise control of composition and architecture, a major limitation is that the mutagenesis is restricted to the 20 naturally occurring amino acids.
Nevertheless, the number of amino acids shown conclusively to exhibit translational activity in vivo is small, and the chemical functionality that has been accessed by this method remains modest.
In designing macr

Method used

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  • Computational method for designing enzymes for incorporation of amino acid analogs into proteins
  • Computational method for designing enzymes for incorporation of amino acid analogs into proteins
  • Computational method for designing enzymes for incorporation of amino acid analogs into proteins

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I. Overview

[0056] The instant invention provides methods and computational tools for modifying the substrate specificity of an AminoAcyl tRNA Synthetases (AARSs) through mutation to enable the enzyme to more efficiently utilize amino acid analog(s) in protein translation systems, either in vitro or in whole cells. A salient feature to the instant invention are methods and tools for systematically redesigning the substrate binding site of an AARS enzyme to facilitate the use of unnatural substrates in the peptide or protein translation reaction the enzyme catalyzes.

[0057] In one embodiment, the subject method uses a rotamer library for the intended amino acid analog (or “analog”), e.g., which represents the coordinates for a plurality of different conformations of the analog resulting from varying torsional angles in the molecule. Members of the rotamer library are modeled in a docking simulation with a model of an AARS, e.g., which includes the coordinates for the substrate binding...

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Abstract

The instant invention provides methods, reagents, and computational tools for designing non-natural substrate analogs for enzymes, especially for designing unnatural amino acid analogs for aminoacyl tRNA Synthetases (AARSs), such as the Phe tRNA Synthetase. The instant invention also provides methods to incorporate unnatural amino acid analogs, especially those with interesting functional groups, into protein products to generate proteins of modified or novel functions.

Description

REFERENCE TO RELATED APPLICATION [0001] This application is a divisional of U.S. patent application Ser. No. 10 / 375,298, filed Feb. 27, 2003 and now allowed, which application claims the benefit under 35 U.S.C. 119(e) of U.S. Provisional Application No. 60 / 360,146, filed on Feb. 27, 2002, the entire contents of each aforementioned application is incorporated herein by reference.GOVERNMENT SUPPORT [0002] Part of this work was supported by NIH Grants R01-GM62523 and T32-GM08501 awarded to the NSF Center for the Science and Engineering of Materials at Caltech. The Government has certain rights in this invention.BACKGROUND OF THE INVENTION [0003] Protein engineering is a powerful tool for modification of the structural catalytic and binding properties of natural proteins and for the de novo design of artificial proteins. Protein engineering relies on an efficient recognition mechanism for incorporating mutant amino acids in the desired protein sequences. Though this process has been ver...

Claims

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Application Information

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IPC IPC(8): C12Q1/68G06F19/00C12N9/22C07K1/00C12N5/06C12N9/00C12N15/00C12P21/02G01N33/48G01N33/50G16B15/30
CPCC07K1/00C07K2299/00C12N9/93G06F19/16G16B15/00G16B15/30
Inventor DATTA, DEEPSHIKHAWANG, PINCARRICO, ISAACMAYO, STEPHENTIRRELL, DAVID
Owner CALIFORNIA INST OF TECH
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