Abstract
Despite decades of investigations, it is not yet clear whether there are rules dictating the specificity of the interaction between amino acids and nucleotide bases. This issue was addressed by determining, in a dataset consisting of 100 high‐resolution protein‐DNA structures, the frequency and energy of interaction between each amino acid and base, and the energetics of water‐mediated interactions. The analysis was carried out using HINT, a non‐Newtonian force field encoding both enthalpic and entropic contributions, and Rank, a geometry‐based tool for evaluating hydrogen bond interactions. A frequency‐ and energy‐based preferential interaction of Arg and Lys with G, Asp and Glu with C, and Asn and Gln with A was found. Not only favorable, but also unfavorable contacts were found to be conserved. Water‐mediated interactions strongly increase the probability of Thr‐A, Lys‐A, and Lys‐C contacts. The frequency, interaction energy, and water enhancement factors associated with each amino acid–base pair were used to predict the base triplet recognized by the helix motif in 45 zinc fingers, which represents an ideal case study for the analysis of one‐to‐one amino acid–base pair contacts. The model correctly predicted 70.4% of 135 amino acid–base pairs, and, by weighting the energetic relevance of each amino acid–base pair to the overall recognition energy, it yielded a prediction rate of 89.7%. © 2008 Wiley Periodicals, Inc. J Comput Chem 2008