The search for local native-like nucleation centers in the unfolded state of β-sheet proteins

Gregory V. Nikiforovich, Carl Frieden

Research output: Contribution to journalArticlepeer-review

10 Scopus citations


An approach involving the systematic computational conformational analysis of all overlapping hexapeptide segments in the protein sequence has found fragments with the higher than average propensity to adopt the native-like three-dimensional structure and other regular nonrandom structures in the unfolded states of four β-sheet proteins, namely IFABP (intestinal fatty acid-binding protein), ILBP (ileal fatty acid-binding protein), CRABP I (cellular retinoic acid-binding protein), and CRBP II (cellular retinal binding protein). The native three-dimensional structures of these four proteins are very similar even though they possess as little as ≈30% sequence similarity. The computational results were validated by comparison with the experimental data of the heteronuclear sequential quantum correlation NMR spectroscopy obtained earlier for IFABP at high urea concentrations. On this basis, a molecular model of the unfolded state of IFABP has been developed. The model presumes a dynamic equilibrium between various nonrandom structures (including the native-like structure) and random coil in the local segments of the protein sequence. The model explains experimental observations obtained earlier for folding of several mutants of IFABP, as well as the observed differences in molecular mechanisms of folding for the four β-sheet proteins. Because the computational approach itself does not employ any experimentally derived information in advance, it is not necessarily limited to the β-sheet proteins.

Original languageEnglish
Pages (from-to)10388-10393
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Issue number16
StatePublished - Aug 2002


Dive into the research topics of 'The search for local native-like nucleation centers in the unfolded state of β-sheet proteins'. Together they form a unique fingerprint.

Cite this