Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 108, Issue 1, Pages 109-113Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1014674107
Keywords
protein folding; hydrogen bonding; beta-turns; helix nucleation
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Funding
- Mathers Foundation
- National Science Foundation
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A protein backbone has two degrees of conformational freedom per residue, described by its phi,psi-angles. Accordingly, the energy landscape of a blocked peptide unit can be mapped in two dimensions, as shown by Ramachandran, Sasisekharan, and Ramakrishnan almost half a century ago. With atoms approximated as hard spheres, the eponymous Ramachandran plot demonstrated that steric clashes alone eliminate 3/4 of phi,psi-space, a result that has guided all subsequent work. Here, we show that adding hydrogen-bonding constraints to these steric criteria eliminates another substantial region of phi,psi-space for a blocked peptide; for conformers within this region, an amide hydrogen is solvent-inaccessible, depriving it of a hydrogen-bonding partner. Yet, this forbidden region is well populated in folded proteins, which can provide longer-range intramolecular hydrogen-bond partners for these otherwise unsatisfied polar groups. Consequently, conformational space expands under folding conditions, a paradigm-shifting realization that prompts an experimentally verifiable conjecture about likely folding pathways.
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