Affinity and specificity of protein U1A-RNA complex formation based on an additive component free energy model.

An MM-GBSA computational protocol was used to investigate wild-type U1A-RNA and F56 U1A mutant experimental binding free energies. The trend in mutant binding free energies compared to wild-type is well-reproduced. Following application of a linear-response-like equation to scale the various energy components, the binding free energies agree quantitatively with observed experimental values. Conformational adaptation contributes to the binding free energy for both the protein and the RNA in these systems. Small differences in DeltaGs are the result of different and sometimes quite large relative contributions from various energetic components. Residual free energy decomposition indicates differences not only at the site of mutation, but throughout the entire protein. MM-GBSA and ab initio calculations performed on model systems suggest that stacking interactions may nearly, but not completely, account for observed differences in mutant binding affinities. This study indicates that there may be different underlying causes of ostensibly similar experimentally observed binding affinities of different mutants, and thus recommends caution in the interpretation of binding affinities and specificities purely by inspection.