Large-Scale Quantitative Assessment of Binding Preferences in Protein–Nucleic Acid Complexes

Abstract

The growing number of high-quality experimental (X-ray, NMR) structures of protein–DNA complexes has sufficient enough information to assess whether universal rules governing the DNA sequence recognition process apply. While previous studies have investigated the relative abundance of various modes of amino acid–base contacts (van der Waals contacts, hydrogen bonds), relatively little is known about the energetics of these noncovalent interactions. In the present study, we have performed the first large-scale quantitative assessment of binding preferences in protein–DNA complexes by calculating the interaction energies in all 80 possible amino acid–DNA base combinations. We found that several mutual amino acid–base orientations featuring bidentate hydrogen bonds capable of unambiguous one-to-one recognition correspond to unique minima in the potential energy space of the amino acid–base pairs. A clustering algorithm revealed that these contacts form a spatially well-defined group offering relatively little conformational freedom. Various molecular mechanics force field and DFT-D ab initio calculations were performed, yielding similar results.

RNA‐protein interactions in an unstructured context

“…Significant progress in understanding nucleobaseamino acid interactions has over the years been made using computational approaches [50, [67][68][69][70][71][72][73][74][75][76][77][78][79][80]. For example, analysis of 3D structures of RNA-or DNA-protein complexes has yielded the relative binding preferences of nucleobases and amino acids together with a geometric and energetic characterization of their interactions [50, 67,68,72,[75][76][77][78][79]. Despite a limited amount of statistics that could be extracted from the analysis of 3D complexes [50], the obtained amino acid preferences for GUA and adenine (ADE) are significantly robust and reproducible when it comes to the scale values and a moderate anticorrelation between the GUA and ADE scales as shown for different sets of RNA-protein complexes (Fig.…”

Representative Amino Acid Side-Chain Interactions in Protein–DNA Complexes: A Comparison of Highly Accurate Correlated Ab Initio Quantum Mechanical Calculations and Efficient Approaches for Applications to Large Systems

“…3 As of March 2014, the Atlas comprised 1,569 unique structures of protein-DNA complexes. Amino acid-nucleotide pairs were extracted from each complex by a procedure based on the SIRIUS set of scripts described by Singh and Thornton.…”

“…A more detailed description of the methodology is provided in our previous study, 3 in which we highlight bioinformatic aspects and features derived from distributions involving tens of thousands of contacts. 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 The cluster representatives for the most stable pair are shown.…”

Amino Acid Interaction (INTAA) web server

“…The IE calculations were performed using parameters derived from AMBER parm94 (DNA) (15) and parm99 (protein) (9,16) classical molecular mechanical force fields and, where applicable, a GB/SA implicit solvent and their technical details were described in detail elsewhere (17,18). The amino acid–deoxyribonucleotide interaction analysis part of the web server allows the user to view the interaction energies of the amino acid–DNA base or amino acid–deoxyribonucleoside monophosphate (dNMP) pairs.…”

“…Up to six such clusters were identified in each distribution as described in our previous works (17,18). In each amino acid cluster within each distribution, a single amino acid–DNA residue pair, called cluster representative, can be defined as the pair containing the amino acid which has the lowest RMSD of the atomic positions from all the other members of that cluster (17,18,20). The amino acid–deoxyribonucleotide interaction analysis web server interface is shown in Figure 2.…”