Poster abstracts

Poster number 30 submitted by Indrajit Deb

Insights into RNA recognition of small molecules using the Fragment Molecular Orbital (FMO) method

Indrajit Deb (Department of Biophysics, University of Michigan, Ann Arbor, Michigan - 48109, USA), Aaron T. Frank (Department of Chemistry and Biophysics, University of Michigan, Ann Arbor, Michigan - 48109, USA)

Abstract:
Predicting the binding affinity between a ligand and a target is the key to optimizing target-ligand interactions and designing bioactive drug-like molecules. Unfortunately, current state-of-the-art empirical methods, when applied to RNA-ligand complexes, exhibit weak correlations between predicted and experimentally measured binding affinities between the RNAs and ligands. Fragment Molecular Orbital (FMO) method1,2 is a divide-and-conquer technique that enables ligand binding energies to be computed using a high-level quantum mechanical (QM) description of the interactions between a ligand and a target receptor.3 Here we describe, to the best of our knowledge, the first reported use of FMO calculations to predict binding energies in RNA-ligand complexes4. We found that FMO calculations could be used to generate reliable estimates of the relative interaction strengths in RNA-ligand complexes. Also, using these FMO calculations, we were able to decompose the binding energies into its specific components and identify component(s) that are dominant. If our preliminary results hold, FMO calculations should find utility as a high-accuracy yet general approach for studying the molecular recognition of small molecule ligands by RNAs associated with human diseases, and in so doing aid is structure-guided design of RNA chemical probes.

References:
1. Kitaura K, Ikeo E, Asada T, Nakano T, Uebayasi M. Fragment molecular orbital method: an approximate computational method for large molecules. Chem. Phys. Lett. 1999, 313, 701-706.
2. Fedorov DG, Ishida T, Kitaura K. Multilayer formulation of the fragment molecular orbital method (FMO). J. Phys. Chem. A. 2005, 109, 2638-2646.
3. Otsuka T, Okimoto N, Taiji M. Assessment and acceleration of binding energy calculations for protein–ligand complexes by the fragment molecular orbital method. J. Comput. Chem. 2015, 36, 2209-2218.
4. Howe JA, Wang H, Fischmann TO, Balibar CJ, Xiao L, Galgoci AM, Malinverni JC, Mayhood T, Villafania A, Nahvi A, Murgolo N. Selective small-molecule inhibition of an RNA structural element. Nature 2015, 526, 672-677.

Keywords: Fragment Molecular Orbital (FMO) method, Binding energy, RNA-ligand complex