Journal
JOURNAL OF MOLECULAR BIOLOGY
Volume 329, Issue 3, Pages 611-622Publisher
ACADEMIC PRESS LTD ELSEVIER SCIENCE LTD
DOI: 10.1016/S0022-2836(03)00423-6
Keywords
protein design; hydrogen bond; energy function; thermodynamic stability; protein core
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Funding
- NIGMS NIH HHS [GM07616] Funding Source: Medline
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Hydrogen bond interactions were surveyed in a set of protein structures. Compared to surface positions, polar side-chains at core positions form a greater number of intra-molecular hydrogen bonds. Furthermore, the majority of polar side-chains at core positions form at least one hydrogen bond to main-chain atoms that are not involved in hydrogen bonds to other main-chain atoms. Based on this structural survey, hydrogen bond rules were generated for each polar amino acid for use in protein core design. In the context of protein core design, these prudent polar rules were used to eliminate from consideration polar amino acid rotamers that do not form a minimum number of hydrogen bonds. As an initial test, the core of Escherichia coli thioredoxin was selected as a design target. For this target, the prudent polar strategy resulted in a minor increase in computational complexity compared to a strategy that did not allow polar residues. Dead-end elimination was used to identify global minimum energy conformations for the prudent polar and no polar strategies. The prudent polar strategy identified a protein sequence that was thermodynamically stabilized by 2.5 kcal/mol relative to wild-type thioredoxin and 2.2 kcal/mol relative to a thioredoxin variant whose core was designed without polar residues. (C) 2003 Elsevier Science Ltd. All rights reserved.
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