Homology modeling of an RNP domain from a human RNA-binding protein: Homology-constrained energy optimization provides a criterion for distinguishing potential sequence alignments.
We have recently described an automated approach for homology modeling using restrained molecular dynamics and simulated annealing procedures (Li et al, Protein Sci., 6:956-970,1997). We have employed this approach for constructing a homology model of the putative RNA-binding domain of the human RNA-binding protein with multiple splice sites (RBP-MS). The regions of RBP-MS which are homologous to the template protein snRNP U1A were constrained by "homology distance constraints," while the conformation of the non-homologous regions were defined only by a potential energy function. A full energy function without explicit solvent was employed to ensure that the calculated structures have good conformational energies and are physically reasonable. The effects of mis-alignment of the unknown and the template sequences were also explored in order to determine the feasibility of this homology modeling method for distinguishing possible sequence alignments based on considerations of the resulting conformational energies of modeled structures. Differences in the alignments of the unknown and the template sequences result in significant differences in the conformational energies of the calculated homology models. These results suggest that conformational energies and residual constraint violations in these homology-constrained simulated annealing calculations can be used as criteria to distinguish between correct and incorrect sequence alignments and chain folds.
Sahasrabudhe
P V
PV
Center for Advanced Biotechnology and Medicine, Piscataway, New Jersey, USA.
Tejero
R
R
Kitao
S
S
Furuichi
Y
Y
Montelione
G T
GT
D000465:Algorithms; D000595:Amino Acid Sequence; D001426:Bacterial Proteins / Q000737:chemistry; D003198:Computer Simulation; D004926:Escherichia coli / Q000737:chemistry; D008958:Models, Molecular; D015233:Models, Statistical; D008969:Molecular Sequence Data; D011487:Protein Conformation; D017433:Protein Structure, Secondary; D011506:Proteins / Q000737:chemistry; D016601:RNA-Binding Proteins / Q000737:chemistry*; D012261:Ribonucleoproteins / Q000737:chemistry*; D016415:Sequence Alignment / Q000379:methods; D017386:Sequence Homology, Amino Acid
D001426:Bacterial Proteins; D011506:Proteins; D016601:RNA-Binding Proteins; D012261:Ribonucleoproteins; C062260:cold shock protein CS7.4, Bacteria