Effects of Energetic Heterogeneity on Protein Folding Dynamics Across Many Non-Homologous Proteins

Abstract

Native structure based models (SBMs, “Go-models”) are based on energy landscape theory and the principle of minimal frustration [1,2]. Using this framework strongly reduces computational demands and allows us to investigate the influence of the contact-energy weight onto the folding process for many different protein families. A large set (approx. 200) of non-homologous monomeric proteins sized from 50-150 amino acids are simulated on a coarse-grained level, representing each amino acid by a single bead. A fully automatized workflow implemented with the help of eSBMTools [3] allows to quantify typical folding properties like phi-values, folding free energy landscapes and transition state ensembles (TSEs) for the simulated proteins.Conventional SBMs use sequence independent homogeneous energy weights for the native contact energy. We compare these “vanilla” models with sequence dependent heterogeneous “flavored” energy weights as introduced by Miyazawa and Jernigan [4]. Subsequently, the dynamics of forming TSEs are compared by the sequential formation of tertiary interfaces between secondary structure elements in vanilla and flavored simulations. We find that, despite the energetic dissimilarity, the sequential ordering is similar between both types of simulations and appears as a robust property. This suggests that protein folding dynamics are strongly influenced by the native protein topology.1. Onuchic, J.N. and P.G. Wolynes, Theory of protein folding. Curr. Opin. Struct. Bio., 2004. 14(1): p. 70-75.2. Schug, A. and J.N. Onuchic, Current opinion in pharmacology, 2010. 10(6): p. 709-14.3. Lutz, B., C. Sinner, G. Heuermann, A. Verma, and A. Schug, eSBMTools1.0: enhanced native structure-based modeling tools. Bioinformatics, 2013. doi:10.1093/bioinformatics/btt478.4. Miyazawa, S. and R.L. Jernigan, Residue-residue potentials with a favorable contact pair term and an unfavorable high packing density term, for simulation and threading. Journal of Molecular Biology, 1996. 256(3): p. 623-44.