Talk abstracts

Talk on Friday 05:05-05:20pm submitted by Keith Van Nostrand

Molecular Mechanics Analysis of Minimum Energy RNA Conformational Dynamics Pathways

Keith P. Van Nostrand (Department of Biochemistry and Biophyics, University of Rochester), Scott D. Kennedy (Department of Biochemistry and Biophyics, University of Rochester), Douglas H. Turner (Department of Chemistry, University of Rochester), David H. Mathews (Department of Biochemistry and Biophyics, University of Rochester)

Abstract:
Conformational changes are important in RNA for both binding and catalysis. A conformational change of a non-canonical pair was modeled computationally. In an NMR structure of an AA mismatch in the sequence:

5’ GGUGAAGGCU3’
3’PCCGAAGCCG 5’

where P is Purine, the AA non-canonical pair was in conformational exchange between a minor and major conformation1. The conversion of the trans Hoogsteen-sugar to a different trans sugar-Hoogsteen non-canonical pair occurs on the order of tens of microseconds.
The AMBER molecular mechanics software package2 was used to model conformational change pathways. Nudged Elastic Band (NEB)3 was used to predict minimal potential energy paths for a series of all-atom images of the system along the path. Predicted pathways from NEB2 were analyzed and a reaction coordinate determined for the conformational change. Umbrella sampling4 was then used to predict the free energy profile5. Umbrella sampling was done using 25 windows of 10 degrees each with 12 ns of sampling per window for 6 different random number seeds. Total sampling involved 1.8 microseconds of MD spanning about 2 years of CPU time. Additionally, the Molecular Mechanics Poisson Boltzmann and Generalized Born Surface Area (MM-PBSA/GBSA) methods were also used to estimate the free energy change between conformations. The opposite relative stability of two structures was predicted, which suggests improvements can be made in the AMBER force field.

References:
1. Chen, et al. 2006. An alternating sheared AA pair and elements of stability for a single
sheared purine-purine flanked by sheared GA pairs in RNA. Biochem. 45:6889-6903
2. Case, et al. 2005. The AMBER Biomolecular Simulation Programs. J. Comp. Chem. 26: 1668-1688
3. Mathews & Case. 2006. Nudged elastic band calculation of minimal energy paths for the
conformational change of a GG non-canonical pair. JMB. 357:1683-1593
4. Torrie & Valleau. 1977. Nonphysical sampling distributions in Monte Carlo free-energy estimation: Umbrella sampling. J. Comp. Phys. 23:187-199
5. Kumar, et al. 1992. The Weighted Histogram Analysis Method for Free Energy Calculations of Biomolecules. J. Comp. Chem. 1992. 13:1011-1021

Keywords: Conformational Change, Molecular Mechanics, Free Energy