Mutagenic effects on protein folding and stability

Knowing how sequence information dictates the formation of protein structure is critical for accurate prediction of structure, for de novo protein design, and for understanding protein folding and misfolding. Based on extensive studies in peptide and protein systems, the pattern of polar and nonpolar amino acids, complementary packing of side chains in the protein core, electrostatic interactions, turns and helix-capping motifs, and secondary-structure propensity have been shown to be important for folding and stability to varying degrees. The pattern of polar and nonpolar residues (binary pattern) in a sequence appears to be most critical for determining the gross three-dimensional fold, whereas other interactions are responsible for the details of protein structure and stability. Residues 9-14 of wild-type P22 Arc repressor form a two-stranded 5-sheet and have the binary pattern of an amphipathic -sheet. Switching two residues in this region (NL11, LN12) results in the formation of two right-handed 310-helices and changes the binary pattern to that of an amphipathic helix. Arc NL11 has an ambiguous binary pattern and is in dynamic equilibrium between the sheet and helical structures. Characterization of mutants in which position 11 is replaced with different hydrophobic residues shows that binary pattern is primarily responsible for determining the structure of this region of Arc. In the context of an ambiguous binary pattern, however, the detailed chemical properties of the position- 1 side chain dictate which of the two competing folds is preferred.

Department dc:contributor.department

Massachusetts Institute of Technology. Dept. of Biology.

Grantor dc:publisher

Massachusetts Institute of Technology

Year dc:date.issued

2002

Author dc:creator

• Anderson, Thomas Anthony, 1973-

Advisor dc:contributor.advisor

• Robert T. Sauer.

• Biology.

Statement dc:rights

• M.I.T. theses are protected by copyright. They may be viewed from this source for any purpose, but reproduction or distribution in any format is prohibited without written permission. See provided URL for inquiries about permission.

Licence dc:rights.uri

• http://dspace.mit.edu/handle/1721.1/7582

Language dc:language.iso

eng

Handle dc:identifier.uri

http://hdl.handle.net/1721.1/8320

OAI identifier oai:identifier

oai:dspace.mit.edu:1721.1/8320