Paper Citing NAMD - Abstract
Xia, Zhen; Zhu, Zhihong; Zhu, Jun; Zhou, Ruhong
Recognition Mechanism of siRNA by Viral p19 Suppressor of RNA Silencing: A Molecular Dynamics Study
BIOPHYSICAL JOURNAL, 96:1761-1769, MAR 4 2009
The p19 protein (p19) encoded from Tombusvirus is involved in various activities such as pathogenicity and virus transport. Recent studies have found that p19 is a plant suppressor of RNA silencing, which binds to short interfering RNAs (siRNAs) with high affinity. We use molecular dynamics (MD) simulations of the wild-type and mutant p19 protein (W39 and W42G) binding with a 21-nt siRNA duplex to study the p19-siRNA recognition mechanism and mutation effects. Our simulations with standard MD and steered molecular dynamics have shown that the double mutant structure is indeed much less stable than the wildtype, consistent with the recent experimental findings. Comprehensive structural analysis also shows that the W39/42G mutations first induce the loss of stacking interactions between p19 and siRNA, Trp(42)-Cyt1 (Cyt1 from the 5' to 3' strand) and Trp(39)-Gua'19 (Gua19 from the 3' to 5'strand), and then breaks the hydrophobic core formed by W39-W42 with nucleotide basepairs in the wildtype. The steered molecular dynamics simulations also show that the mutant p19 complex is "decompounded" very fast under a constant separation force, whereas the wild-type remains largely intact under the same steering force. Moreover, we have used the free energy perturbation to predict a binding affinity loss of 6.98 +/- 0.95 kcal/mol for the single mutation W39G, and 12.8 +/- 1.0 kcal/mol loss for the double mutation W39/42G, with the van der Waals interactions dominating the contribution (similar to 90%). These results indicate that the W39/42G mutations essentially destroy the important p19-siRNA recognition by breaking the strong stacking interaction between Cyt1 and Gua'19 with end-capping tryptophans. These large scale simulations might provide new insights to the interactions and co-evolution relationship between RNA virus proteins and their hosts.
