The project is Specific Aim 2 of Project IV of the resource. Although there a variety of programs for performing molecular dynamics simulations of biomolecules, fewer codes are available for generating starting conformations, particularly when crystal of NMR structures are not available.
This specific aim will build upon experience in the Case and Harvey groups, creating computer languages and programming environments that are designed to facilitate model-building and exploration in large systems. We plan to merge some existing efforts in these directions, to create and distribute a flexible and intuitive language for the creation of molecular models for large systems. Our initial efforts have revolved around obtaining initial structural models at low resolution for the 30S subunit of the E. Coli ribosome. The progress in collecting experimental data and constructing mechanical models is described elsewhere in this progress report. Here we concentrate on the software aspects of this effort. The Harvey group has a long-standing project in making models for ribonucleic acid particles of this type, and are experienced in creating """"""""descriptors"""""""" in the yammp environment (developed in the Harvey group at UAB) that allow manipulation of such models. These descriptors are low-level lists of bonds, angles, torsions, etc. in the final models. We have written code in NAB (nucleic acid builder) to convert these descriptor files into bounds matrices, for use in distance geometry calculations, and into Amber-style parameter and topology (""""""""prmtop"""""""") files. This is a first, but key, step in connecting the yammp capabilities into those of more conventional simulation packages like Amber or CHARMM. The experience gained here on a large model (with about 1700 nucleic acid bases and 21 proteins represented as spheres) has also lead to considerable improvements in the distance geometry codes in NAB. In particular, we have been able to use bounds smoothing to identify specific inconsistencies in experimental data, and to extend the computer codes to analyze and report these in a better fashion, and to embed very large initial models with more reliability. Plans for the next year are completion of Amber and CHARMM libraries for use with these reduced models, adding additional functional forms into Amber to mimic those in yammp, and the use of this functionality to carry out molecular dynamics simulated annealing refinements of these structures using the parallel processing capabilities of Amber.
| 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 |
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| 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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