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Secondary structure determines protein topology

T.C. Jenkins Department of Biophysics, Johns Hopkins University, Baltimore, Maryland 21218, USA

(RECEIVED April 24, 2006; FINAL REVISION April 24, 2006; ACCEPTED May 18, 2006)

Using a test set of 13 small, compact proteins, we demonstrate that a remarkably simple protocol can capture native topology from secondary structure information alone, in the absence of long-range interactions. It has been a long-standing open question whether such information is sufficient to determine a protein's fold. Indeed, even the far simpler problem of reconstructing the three-dimensional structure of a protein from its exact backbone torsion angles has remained a difficult challenge owing to the small, but cumulative, deviations from ideality in backbone planarity, which, if ignored, cause large errors in structure. As a familiar example, a small change in an elbow angle causes a large displacement at the end of your arm; the longer the arm, the larger the displacement. Here, correct secondary structure assignments (-helix, -strand, -turn, polyproline II, coil) were used to constrain polypeptide backbone chains devoid of side chains, and the most stable folded conformations were determined, using Monte Carlo simulation. Just three terms were used to assess stability: molecular compaction, steric exclusion, and hydrogen bonding. For nine of the 13 proteins, this protocol restricts the main chain to a surprisingly small number of energetically favorable topologies, with the native one prominent among them.

Keywords: protein topology; protein folding; secondary structure; hydrogen bonding; confinement

Reprint requests to: George D. Rose, T.C. Jenkins Department of Biophysics, Johns Hopkins University, 3400 N. Charles Street, Baltimore, MD 21218; e-mail: grose{at}jhu.edu; fax: (410) 516-4118.

Article published online ahead of print. Article and publication date are at http://www.proteinscience.org/cgi/doi/10.1110/ps.062305106.

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