Homology modeling of an RNP domain from a human RNA-binding protein: Homology-constrained energy optimization provides a criterion for distinguishingpotential sequence alignments
Pv. Sahasrabudhe et al., Homology modeling of an RNP domain from a human RNA-binding protein: Homology-constrained energy optimization provides a criterion for distinguishingpotential sequence alignments, PROTEINS, 33(4), 1998, pp. 558-566
We have recently described an automated approach for homology modeling usin
g restrained molecular dynamics and simulated annealing procedures (Li et a
l, Protein Sci,, 6:956-970,1997), We have employed this approach for constr
ucting a homology model of the putative RNA-binding domain of the human RNA
-binding protein with multiple splice sites (REP-MS), The regions of REP-MS
which are homologous to the template protein snRNP U1A were constrained by
"homology distance constraints," while the conformation of the non-homolog
ous regions were defined only by a potential. energy function. A full energ
y function without explicit solvent was employed to ensure that the calcula
ted structures have good conformational energies and are physically reasona
ble. The effects of misalignment of the unknown and the template sequences
were also explored in order to determine the feasibility of this homology m
odeling method for distinguishing possible sequence alignments based on con
siderations of the resulting conformational energies of modeled structures.
Differences in the alignments of the unknown and the template sequences re
sult in significant differences in the conformational energies of the calcu
lated homology models, These results suggest that conformational energies a
nd residual constraint violations in these homology-constrained simulated a
nnealing calculations can be used as criteria to distinguish between correc
t and incorrect sequence alignments and chain folds. (C) 1998 Wiley-Liss, I
nc.