title: Probabilistic search and energy guidance for biased decoy sampling in ab initio protein structure prediction.
abstract: Adequate sampling of the conformational space is a central challenge in ab initio protein structure prediction. In the absence of a template structure, a conformational search procedure guided by an energy function explores the conformational space, gathering an ensemble of low-energy decoy conformations. If the sampling is inadequate, the native structure may be missed altogether. Even if reproduced, a subsequent stage that selects a subset of decoys for further structural detail and energetic refinement may discard near-native decoys if they are high energy or insufficiently represented in the ensemble. Sampling should produce a decoy ensemble that facilitates the subsequent selection of near-native decoys. In this paper, we investigate a robotics-inspired framework that allows directly measuring the role of energy in guiding sampling. Testing demonstrates that a soft energy bias steers sampling toward a diverse decoy ensemble less prone to exploiting energetic artifacts and thus more likely to facilitate retainment of near-native conformations by selection techniques. We employ two different energy functions, the associative memory Hamiltonian with water and Rosetta. Results show that enhanced sampling provides a rigorous testing of energy functions and exposes different deficiencies in them, thus promising to guide development of more accurate representations and energy functions.
authors.affiliation: George Mason University, Fairfax.
authors.forename: Kevin
authors.initials: K
authors.lastname: Molloy
authors.affiliation: George Mason University, Fairfax.
authors.forename: Sameh
authors.initials: S
authors.lastname: Saleh
authors.affiliation: George Mason University, Fairfax.
authors.forename: Amarda
authors.initials: A
authors.lastname: Shehu
mesh_terms: D003198:Computer Simulation; D004735:Energy Transfer; D008956:Models, Chemical; D008958:Models, Molecular; D015233:Models, Statistical; D011487:Protein Conformation; D011506:Proteins / Q000737:chemistry* / Q000648:ultrastructure*; D018401:Sample Size
chemical_list: D011506:Proteins