Solvent Accessibility Promotes Rotamer Errors during Protein Modeling with Major Side-Chain Prediction Programs

Side-chain rotamer prediction is one of the most criticallatestages in protein 3D structure building. Highly advanced and specializedalgorithms (e.g., FASPR, RASP, SCWRL4, and SCWRL4v) optimize thisprocess by use of rotamer libraries, combinatorial searches, and scoringfunctions. We seek to identify the sources of key rotamer errors asa basis for correcting and improving the accuracy of protein modelinggoing forward. In order to evaluate the aforementioned programs, weprocess 2496 high-quality single-chained all-atom filtered 30% homologyprotein 3D structures and use discretized rotamer analysis to compareoriginal with calculated structures. Among 513,024 filtered residuerecords, increased amino acid residue-dependent rotamer errors Rassociatedin particular with polar and charged amino acid residues (ARG, LYS,and GLN)Rclearly correlate with increased amino acid residuesolvent accessibility and an increased residue tendency toward theadoption of non-canonical off rotamers which modeling programs struggleto predict accurately. Understanding the impact of solvent accessibilitynow appears key to improved side-chain prediction accuracies.