Computational Analysis of Protein Dynamics
The static pictures of protein structures obtained from crystallography need to be complemented by information about the dynamics of the protein atoms as well as those of any ligands and the solvent (water and ions). Experimental techniques such as NMR and fluorescence spectroscopy can provide windows into dynamics but the information obtained can be quite limited. Computer simulations of protein dynamics (molecular dynamics simulations) are useful because they provided detailed information about dynamics in all parts of the structure and solvent. The severe limitations of simulations have to do with how realistic they are, and these arise from limitations in computer intermolecular interactions are described.
Despite questions about how well molecular dynamics simulations reflect reality, we find them to be very useful because they help us to map flexible and rigid parts of the structures and to understand whether portions of the protein structure are under strain. We have used molecular dynamics simulations to study the Src family tyrosine kinases and the DNA polymerase clamp loading process. Click here to see a quicktime movie of the molecules motion at room temperature. Information on these projects can be found here:
Matthew A. Young, Stefania Gonfloni, Giulio
Superti-Furga, Benoit Roux and John Kuriyan
Dynamic Coupling
Between the
SH2 and SH3 Domains of C-Src and Hck Underlies Their Inactivation by C-Terminal Tyrosine
Phosphorylation
David Jeruzalmi, Olga Yurieva, Yanxiang Zhao,
Matthew Young, Jelena Stewart,
Manju Hingorani, Mike O'Donnell and John Kuriyan Mechanism of Processivity
Clamp Opening by the Delta-subunit Wrench of the Clamp Loader Complex of E. coli DNA Polymerase
III
In the future we plan to investigate how we can use these simulations to obtain information about long time scale phenomena (such as the conformational dynamics of the activation loop in protein kinases) and about the differences in free energy between different conformational states of the protein.
Useful references on molecular dynamics are given here:
- Elcock, A.H. (2002). Modeling supramolecular assemblages. Curr Opin Struct Biol 12, 154-160.
- McCammon, J.A. and P.G. Wolynes (2002). Enlarging the landscape. Curr Opin Struct Biol 12, 143-145.
- Hansson, T., C. Oostenbrink, and W. van Gunsteren (2002). Molecular dynamics simulations. Curr Opin Struct Biol 12, 190-196.
- Mattos, C. (2002). Protein-water interactions in a dynamic world. Trends Biochem Sci 27, 203-208.