Protein flexibility and rigidity predicted from sequence.

TitleProtein flexibility and rigidity predicted from sequence.
Publication TypeJournal Article
Year of Publication2005
AuthorsSchlessinger, A, Rost, B
Date Published2005 Oct 1
KeywordsAmino Acid Sequence, Binding Sites, Databases, Protein, Evolution, Molecular, Nuclear Magnetic Resonance, Biomolecular, Pliability, Protein Structure, Secondary, Protein Structure, Tertiary, Proteins, Solvents

Structural flexibility has been associated with various biological processes such as molecular recognition and catalytic activity. In silico studies of protein flexibility have attempted to characterize and predict flexible regions based on simple principles. B-values derived from experimental data are widely used to measure residue flexibility. Here, we present the most comprehensive large-scale analysis of B-values. We used this analysis to develop a neural network-based method that predicts flexible-rigid residues from amino acid sequence. The system uses both global and local information (i.e., features from the entire protein such as secondary structure composition, protein length, and fraction of surface residues, and features from a local window of sequence-consecutive residues). The most important local feature was the evolutionary exchange profile reflecting sequence conservation in a family of related proteins. To illustrate its potential, we applied our method to 4 different case studies, each of which related our predictions to aspects of function. The first 2 were the prediction of regions that undergo conformational switches upon environmental changes (switch II region in Ras) and the prediction of surface regions, the rigidity of which is crucial for their function (tunnel in propeller folds). Both were correctly captured by our method. The third study established that residues in active sites of enzymes are predicted by our method to have unexpectedly low B-values. The final study demonstrated how well our predictions correlated with NMR order parameters to reflect motion. Our method had not been set up to address any of the tasks in those 4 case studies. Therefore, we expect that this method will assist in many attempts at inferring aspects of function.

Alternate JournalProteins
PubMed ID16080156
Grant ListR01-GM63029-01 / GM / NIGMS NIH HHS / United States
R01-LM07329-01 / LM / NLM NIH HHS / United States