Onuchic Research group

A very brief introduction to structure-based modeling

Structure-based models have had considerable success in expanding our understanding of biomolecular folding and function. Many models have been coarse-grained, such that each residue is represented by a single bead. Recent work in our group has been to extend the C-alpha model to an all-atom representation for structure-based simulations of biomolecules (complete descriptions of Protein and RNA/DNA models). In contrast to several previous models, this class of models not only includes all heavy (non-hydrogen) atoms, but it is also completely structure-based. That is, the global energetic minimum is the native structure (as determined by the PDB structure).

For many applications, a completely structure-based model will be sufficient to provide realistic dynamics. But, for some observables, such as shifts in populations associated with phosphorylation or changes in pH, this model may be overly simplified. Fear not, with the flexibility of molecular dynamics software packages, it is simple to include additional interactions and/or perturbations to your atomic system. This can elucidate both large length and long time scale dynamics and short time scale dynamics with atomic resolution. This model is not only malleable to your specific needs, but it is also computationally less expensive than many other simulation methods.

Practical matters: Going from a structure to a simulation

Since not everyone is familiar with the nuts and bolts of structure-based modeling, these simple steps will take you through it.

Step 0: Install and familiarize yourself with the Gromacs molecular simulation package (Version 4). Gromacs will be the engine of the simulations. There are several excellent general tutorials available on the Gromacs webpage. We use Gromacs for our model because it a) is easy to use, b) has many available options and c) has an excellent analysis suite.

Step 1: Prepare the structure-based potential input files for Gromacs (All-atom or C-Alpha). Since this model is not included in any major software distribution, we have made it freely available through our web interface. All you need to do is provide a pdb structure file and specify which parameters you would like to use, and we will generate the Gromacs input files for you.

Step 2: Run the simulation. Since structure-based models are slightly different from many other simulation protocols, there are a few things to keep in mind when simulating your system. Click here for a step-by-step description of how to run your simulation in Gromacs. Even if you are familiar with Gromacs, you should take a quick look at this information, to ensure all settings are reasonable.

Step 3: Analyze the results. Once you have the completed simulations, it's time to look at the results. In addition to all of the analysis modules available with your Gromacs distribution, we will continually make more scripts and programs available to the public here. If you have written your own analysis script that you beleive may be useful to others, please send us a copy and we will make it available.

Primary References:

Whitford PC, Noel JK, Gosavi S, Schug A, Sanbonmatsu KY & Onuchic JN (2009) "An all-atom structure-based potential for proteins: Bridging minimal models with all-atom empirical forcefields." PROTEINS DOI: 10.1002/prot.22253.

Whitford PC, Schug A, Saunders J, Hennelly SP, Onuchic JN & Sanbonmatsu KY (2009) "Non-local helix formation is key to understanding S-adenosylmethionine-1 riboswitch function." Biophys. J. 96, L7-9. DOI: 10.1016/j.bpj.2008.10.033.

For the C-alpha model: Clementi C, Nymeyer H & Onuchic JN (2000) "Topological and energetic factors: What determines the structural details of the transition state ensemble and En-route intermediates for protein folding? An Investigation for small globular proteins." J. Mol. Biol. 298, 937-953. DOI:10.1006/jmbi.2000.3693

Please direct questions and comments to sbm-help@ctbp.ucsd.edu.
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