Strategy for supplementing structure calculations using limited data with hydrophobic distance restraints.
Introductory biochemistry texts often note that the fold of a protein is completely defined when the dihedral angles phi and psi are known for each amino acid. This assertion was examined with torsion angle dynamics and simulated annealing (TAD/SA) calculations of protein G using only dihedral angle restraints. When all dihedral angles were restrained to within 1 degrees of the values of the X-ray structure, the TAD/SA structures gave a backbone root mean square deviation to the target of 4 A. Factors that contributed to divergence from the correct solution include deviations of peptide bonds from planarity, internal conflicts resulting from the nonuniform energies of different phi, psi combinations, and relaxation to extended conformations in the absence of long-range constraints. Simulations including hydrogen-bond restraints showed that even a few long-range contacts constrain the fold better than a complete set of accurate dihedral restraints. A procedure is described for TAD/SA calculations using hydrogen-bond restraints, idealized dihedral restraints for residues in regular secondary structures, and "hydrophobic distance restraints" derived from the positions of hydrophobic residues in the amino acid sequence. The hydrogen-bond restraints are treated as inviolable, whereas violated hydrophobic restraints are removed following reduction of restraint upper bounds from 2 to 1 times the predicted radius of gyration. The strategy was tested with simulated restraints from X-ray structures of proteins from different fold classes and NMR data for cold shock protein A that included only backbone chemical shifts and hydrogen bonds obtained from a long-range HNCO experiment.
Alexandrescu
Andrei T
AT
Department of Molecular and Cell Biology, University of Connecticut, Storrs, Connecticut 06269-3125, USA. andrei@uconn.edu
D003198:Computer Simulation; D018360:Crystallography, X-Ray; D006860:Hydrogen Bonding; D057927:Hydrophobic and Hydrophilic Interactions; D009682:Magnetic Resonance Spectroscopy; D008958:Models, Molecular; D011487:Protein Conformation; D017510:Protein Folding; D011506:Proteins / Q000737:chemistry* / Q000378:metabolism; D012680:Sensitivity and Specificity
D011506:Proteins