Alchemical free energy to probe RNA/ligand interactions.

Abstract

Alchemical free energy calculations are increasingly being applied in academic research as well as in the pharmaceutical industry. These methods originate in theories of Kirkwood and Zwanzig, where Kirkwood introduced a coupling parameter approach, and Zwanzig showed that the free energy difference between two states can be computed via an appropriate exponential average of energy differences over an ensemble of configurations. In recent years, alchemical free energy calculations have benefited from improved force fields, new sampling algorithms, and the emergence of parallel computing, which have been shown to yield accurate results. These calculations are routinely applied to large-scale free energy calculations for ligand modification, and for testing mutations in amino acids and nucleotides. Here, we report alchemical calculations on RNA/peptide and RNA/small-molecule complexes, which are conducted using free energy perturbation (FEP) and thermodynamic integration (TI) methods. We discovered that the peptides employ base-specific hydrogen bonding, sugar-phosphate backbone interactions, and cation-pi interactions for the recognition of RNA molecules. In contrast, the small molecules recognize the RNA via base-specific and pi-pi stacking interactions.