This core project is devoted to developing, testing, and applying hybrid sampling methods to explore protein and peptide folding thermodynamics and dynamics. These objectives will be achieved by integrating the rapid and extensive conformational search tools of lattice Monte Carlo with the more accurate protein representations provided by all atom, explicit solvent molecular dynamics methods, such as developed and used in the CHARMM molecular modeling package. As a testbed for this development, the folding of a number of small proteins and protein fragments such as the GCN4 leucine zipper will be examined. We have developed a code for the rapid conversion from reduced models to full atom models and vice versa. Thus, we can now routinely provide all atom models for input into the CHARMM package starting from a lattice model of the a-carbon coordinates. First, the backbone coordinates are rapidly generated. Then, side chain atoms are built using the Internal Coordinate table of CHARMM, followed by a short energy minimization step. In a series of preliminary studies, Entropy Sampling Monte Carlo of the lattice model of the GCN4 leucine zipper has been performed to provide a full characterization of the free energy landscape which can be compared to that obtained from the full atom models. Evaluation of the full atom unfolding trajectories shows that the energy in the reduced model is highly correlated with the root-mean-square deviation of the alpha carbon positions from their native conformation. This provides encouragement that the empirical energies in the reduced model and that of the detailed atomic models are highly correlated, and thus, we can proceed to the development of multiresolution conformational sampling tools. In collaboration with Ron Elber, who is a Professor of Chemistry at Hebrew University, we have begun the integration of the Onsager-Machlup approach with lattice simulations to explore the dynamics of peptide folding. During his visit to Scripps in February, 1998, a series of conformations of protein G at various distances from native were provided. He is now undertaking a path integral study of the folding pathway of protein G, by interpolating between various conformations at different distances from the native state. This will provide experience on the ability to simulate folding pathways using these combined approaches. Goals for the coming year include (1). Development and testing of a more accurate side chain rebuilding protocol. (2). Development of the combined lattice Monte-Carlo-full atom multiresolution conformational sampling protocols. (3) Evaluation of these protocols on a series of short peptides. (4). Compilation of a library of near native and misfolded states with which to assess the viability of Elber's path integral approach to protein dynamics.
| Salmon, Loïc; Ahlstrom, Logan S; Horowitz, Scott et al. (2016) Capturing a Dynamic Chaperone-Substrate Interaction Using NMR-Informed Molecular Modeling. J Am Chem Soc 138:9826-39 |
| Bruno, Paul A; Morriss-Andrews, Alex; Henderson, Andrew R et al. (2016) A Synthetic Loop Replacement Peptide That Blocks Canonical NF-?B Signaling. Angew Chem Int Ed Engl 55:14997-15001 |
| Montiel-García, Daniel J; Mannige, Ranjan V; Reddy, Vijay S et al. (2016) Structure based sequence analysis of viral and cellular protein assemblies. J Struct Biol 196:299-308 |
| Rosen, Laura E; Kathuria, Sagar V; Matthews, C Robert et al. (2015) Non-native structure appears in microseconds during the folding of E. coli RNase H. J Mol Biol 427:443-53 |
| Cheng, Shanshan; Brooks 3rd, Charles L (2015) Protein-Protein Interfaces in Viral Capsids Are Structurally Unique. J Mol Biol 427:3613-3624 |
| Carrillo-Tripp, Mauricio; Montiel-García, Daniel Jorge; Brooks 3rd, Charles L et al. (2015) CapsidMaps: protein-protein interaction pattern discovery platform for the structural analysis of virus capsids using Google Maps. J Struct Biol 190:47-55 |
| Ahlstrom, Logan S; Law, Sean M; Dickson, Alex et al. (2015) Multiscale modeling of a conditionally disordered pH-sensing chaperone. J Mol Biol 427:1670-80 |
| Taylor, Kenneth A; Feig, Michael; Brooks 3rd, Charles L et al. (2014) Role of the essential light chain in the activation of smooth muscle myosin by regulatory light chain phosphorylation. J Struct Biol 185:375-82 |
| Zeng, Xiancheng; Chugh, Jeetender; Casiano-Negroni, Anette et al. (2014) Flipping of the ribosomal A-site adenines provides a basis for tRNA selection. J Mol Biol 426:3201-3213 |
| Vashisth, Harish; Skiniotis, Georgios; Brooks 3rd, Charles Lee (2014) Collective variable approaches for single molecule flexible fitting and enhanced sampling. Chem Rev 114:3353-65 |
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