Development

Realistic simulation of biological macromolecules in solution necessitates rigorous molecular dynamics (MD) methods. As such, improving the fidelity of our MD calculations is of great interest to our lab, as is including other biologically or experimentally relevant cosolvents, ligands, etc. To these ends, we actively develop new force-field parameters for necessary molecules that in simulation reproduce experimental qualities of the target molecules.

When the simulations are complete, we run a large suite of analyses for interpreting the trajectory and for comparison to experimental observables from NMR experiments, CD, etc. As new techniques are developed, in NMR for example, we have developed new analyses to use to evaluate our simulations against experiment.

To these ends, we have developed in lucem Molecular Mechanics (ilmm), a scalable parallel molecular mechanics engine for:

• Molecular dynamics (MD) simulation of proteins in:
  • Explicit solvent (water)
  • Explicit co-solvents such as water, urea, gndHCl, TMAO, etc. or mixtures of these
  • Membranes or anchored to membranes (via GPI)
• Analysis of MD simulations, including:
  • Structure comparison (RMSD, CONGENEAL)
  • Dihedral reporting and Phi/Psi statistics
  • Solvent accessible surface area (SASA)
  • Identification of intra and intermolecular contacts
  • NMR NOE, order parameters (S2) and residual dipolar coupling (RDC)
  • Diffusion, radial distribution function, solvent density function
• Other features:
  • Minimization
  • Simulated annealing
  • Replica-exchange molecular dynamics
  • Distance geometry
  • Embedded version for use in Perl and Python
  • Direct interfaces to UCSF Chimera and Pymol

We have also created an XML Schema for describing general molecular mechanics parameter libraries which we now use with our simulation engine. See a graphical representation and read more about it here.

Relevant Publications

• Beck D.A.C., Alonso D.O.V., and Daggett V. (2000-2009) in lucem Molecular Mechanics (ilmm), University of Washington, Seattle.
• Beck D.A.C. and Daggett V. Methods for Molecular Dynamics Simulations of Protein Folding/Unfolding in Solution, Methods 34: 112-120, 2004. [DOI]
• Beck D.A.C., Armen R.S., and Daggett V. Cutoff size need not strongly influence molecular dynamics results on solvated polypeptides. Biochemistry 44: 609-616, 2005. [DOI]
• Beck D.A.C., Alonso D.O.V., Inoyama D., and Daggett V. The intrinsic conformational propensities of the 20 naturally occurring amino acids and reflection of these propensities in proteins. Proceedings of the National Academy of Sciences USA 105: 12259-12264, 2008. [DOI]