Probing Protein Fold Space with a Simplified Model

• Published in: Journal of molecular biology Vol. 375; no. 4; pp. 920 - 933
• Main Authors: Minary, Peter, Levitt, Michael
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier Ltd 25.01.2008
• Subjects: Amino Acid Sequence; coarse-grained statistical potentials; Computer Simulation; Databases, Protein; Energy Transfer; Markov Chains; Models, Molecular; Molecular Sequence Data; Monte Carlo Method; multicanonical sampling; multidimensional scaling; near-native energy landscape; Protein Conformation; Protein Denaturation; protein fold space; Protein Folding; Protein Structure, Secondary; Protein Structure, Tertiary; Proteins - chemistry; Proteins - metabolism; Software; Temperature; Thermodynamics; coarse-grained statistical potentials; PT; MC; EEMC; near-native energy landscape; protein fold space; multidimensional scaling; multicanonical sampling
• ISSN: 0022-2836; 1089-8638; 1089-8638
• DOI: 10.1016/j.jmb.2007.10.087

We probe the stability and near-native energy landscape of protein fold space using powerful conformational sampling methods together with simple reduced models and statistical potentials. Fold space is represented by a set of 280 protein domains spanning all topological classes and having a wide range of lengths (33–300 residues) amino acid composition and number of secondary structural elements. The degrees of freedom are taken as the loop torsion angles. This choice preserves the native secondary structure but allows the tertiary structure to change. The proteins are represented by three-point per residue, three-dimensional models with statistical potentials derived from a knowledge-based study of known protein structures. When this space is sampled by a combination of parallel tempering and equi-energy Monte Carlo, we find that the three-point model captures the known stability of protein native structures with stable energy basins that are near-native (all α: 4.77 Å, all β: 2.93 Å, α/β: 3.09 Å, α+β: 4.89 Å on average and within 6 Å for 71.41%, 92.85%, 94.29% and 64.28% for all-α, all-β, α/β and α+β, classes, respectively). Denatured structures also occur and these have interesting structural properties that shed light on the different landscape characteristics of α and β folds. We find that α/β proteins with alternating α and β segments (such as the β-barrel) are more stable than proteins in other fold classes.