1. Molecular Dynamics and Normal Mode Analysis of WW domain Santanu Chatterjee 1, Christopher Sweet 1, Tao Peng 2, John Zintsmaster 2, Brian Wilson 2, Jesus A. Izaguirre 1 & Jeffrey Peng 2 1 Department of Computer Science and Engineering, University of Notre Dame 2 Department of Chemistry and Biochemistry, University of Notre Dame Objective -Analyze conformational transitions of Pin-1 WWdomain due to binding to a peptide(cdc25). - Atomistic MD simulation is accurate for fast timescale dynamics (ps-ns). -Comparing MD trajectory with NMR is difficult due shorter timescale of accessible trajectory. -How can one find a reduced representation capable of approximating dynamical features over a long timescale? Normal Mode Analysis Suitable for qualitative study of large amplitude deformational motions of biomolecules. Represent collective motions of atoms in a coupled system. Main assumption is that energy surface is quadratic in the vicinity energy minimum. Interatomic potential is approximated by a pair wise Hookean spring potential (Tirion, 1996) Diagonalization of the linear force matrix results in the normal modes (eigenvectors) of the system as well as the frequency of normal modes A non-linear molecule with N atoms has 3N-6 normal modes. Can conformational change be studied by Normal Mode analysis? Results. How well can we estimate the conformational difference between the flexible loop? How does the dominant eigenvectors translate rigid and flexible parts from source to target? Flexiblity in WWdomain NMR studies detected flexibility in the recognition loop of apo-WW domain (residues 11-17). Twisting motion visible from the analysis of Minimum Energy Path connecting Pin-1 WWdomain with the bound conformation with cdc25 peptide (using MOIL softwarehttp://cbsu.tc.cornell.edu/software/moil/).http://cbsu.tc.cornell.edu/software/moil/ -Is it possible to generate to find a path between two conformational states? -A reduced description of the system can help us simulate ignoring many fast degrees of freedom? Conformational Change Given two conformations of proteins A and B, if we consider B a small perturbation from the equilibrium position A, a first order approximation of B (Petrone and Pande, 2006). The matrix of eigenvectors can be mapped into normal mode coordinates by a linear transformation: Results: Normal Mode Amplitudes How close is the mapped structure with that of target? Conclusions A set of normal modes can be useful describing conformational change. However, it is essential to measure relative importance of various modes, since dominant modes can be of high frequency ones (localized motions). Set of dominant eigenmodes can be used to enhance timescales of simulations ( reduced descriptions, reaction coordinates). Acknowledgements This work has been partly supported by NSF DBI- 0450067. References: P. Petrone and V.S.Pande, Can conformational change be described be described by only a few normal modes?, Biophysical Journal, 2006, Vol. 90, 1583-1983. S.A.Showalter, N.A.Baker, C.Tang and K.B.Hall, Iron responsive element RNA flexibility described by NMR and isotropic reorientational eigenmode dynamics, Journal of Biomolecular NMR, 2005, Vol. 32, 179- 193. F. Tama and Y.H. Sanejouand, Conformational change of protein arising from Normal Mode calculations, Protein Engg., 2001, Vol. 14, 1-6. R. Elber, Long timescale simulation methods, Curr. Opin. Struct. Biol., 2005, Vol. 15, 151-156. M. M. Tirion, Large amplitude elastic motions in proteins from a single- parameter atomic analysis, Phys. Rev. Lett., 1996, Vol. 77, 1905-1908. R. Elber, A. Ghosh, A. Cardenas and H. Stern, Bridging the gap between reaction pathways, long time dynamics and calculation of rates, Advances in Chemical Physics,2003, Vol. 126, 93-129.