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Published June 6, 2003 | public
Journal Article

Prudent modeling of core polar residues in computational protein design


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.

Additional Information

© 2003 Elsevier Science Ltd. Received 26 February 2003; accepted 19 March 2003. Edited by M. Levitt. Available online 21 May 2003. We thank P. S. Shah for aid in protein expression and purification, P. Strop for helpful discussions and M. Ary for critical comments on the manuscript. This research was supported by the Howard Hughes Medical Institute and the Ralph M. Parsons Foundation (S.L.M.), the Helen G. and Arthur McCallum Foundation, the Evelyn Sharp Graduate Fellowship, and grant GM07616 from the National Institutes of Health (D.N.B.).

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