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THIS TALK HAS BEEN CANCELLED DUE TO HAZARDOUS WEATHER AND TRAVEL CONDITIONS.  WE ARE IN THE PROCESS OF RESCHEDULING.  

Dr. David Case is a distinguished professor at Rutgers University.  His research consists of the theoretical chemistry of biomolecules. Particular areas of interest include molecular dynamics simulations of proteins and nucleic acids; electronic structure calculations of transition-metal complexes that model active sites in metalloenzymes; development and application of methods for NMR structure determination; ligand-protein and ligand-nucleic acid docking and computational drug design.

Dr. Case will be in Buffalo on March 22nd to give a talk based on his research.  Details below.

Date & Time:  March 22nd, 2018 at 3PM EST

Location:  Hauptman Woodward Institute, 700 Ellicott Street, Buffalo, NY 14203

Room:  Flickinger Lecture Hall 1F

What can we learn from MD simulations of biomolecular crystals? 

Case, David A. 

Dept. of Chemistry and Chemical Biology, Rutgers University, Piscataway, NJ 08854 USA 

The adaption of graphical processing units (GPUs) to biomolecular simulations has made microsecond-scale simulations of biomolecular crystals available on a nearly-routine basis [1-5].  Typically, a super-cell consisting of several crystallographic unit cells becomes the periodically-repeating unit in the simulation; in this talk, I will consider super-cells with up to 125 unit cells.  Here are some ways this data might be used:

• Straightforward comparisons between computed and experimental average structures and atomic displacement parameters can be used to identify problems in biomolecular force fields [1-4].  The high accuracy and precision crystallography (compared to NMR or other solution methods) makes such comparisons uniquely informative, and the statistics of such comparisons benefit from having many copies of chains in equivalent environments in the simulation.
• Structural fluctuations in the simulations can be used to estimate diffuse scattering intensities, which can be compared to recent measurements using modern detectors [5,6].  I will show examples of results for lysozyme in three crystal forms, using data collected at CHESS by Steve Mesiburger and Nozomi Ando as a reference.  These provide important insights into the contributions to diffuse scatter from water and from lattice vibrations of the protein.
• Simulations provide a model for density fluctuations in regions of "disordered" or "bulk" solvent (mainly water).  Such models appear to account for solvent contributions to Bragg intensities in ways that are a systematic improvement over the procedures used in most protein structure refinement protocols.
• Simulations provide a plausible, if imperfect, model for conformational heterogeneity in biomolecular crystals.  Having both Bragg intensities computed from the average electron density (as a refinement target) and hints from the trajectory itself as to the nature of the underlying conformational transitions, James Holton has created and refined atomic models with many more than the traditional number of "alternate locations"; these can closely reproduce the synthetic Bragg intensities. We hope that such models may provide clues about how to construct better models to refine against real data.
• TeraHertz spectroscopy in biomolecular crystals, and its orientation dependence [7], can be directly compared to predictions from MD simulations.

[1] D.S. Cerutti, P.L. Freddolino, R.E. Duke and David A. Case. Simulations of a protein crystal with a high resolution X-ray structure: Evaluation of force fields and water models. J. Phys. Chem. B 114, 12811-12824 (2010).

[2] P.A. Janowski, D.S. Cerutti, J. Holton and D.A. Case. Peptide crystal simulations reveal hidden dynamics. J. Am. Chem. Soc. 135, 7938-7948 (2013).

[3] C. Liu, P.A. Janowski and D.A. Case. All-atom crystal simulations of DNA and RNA duplexes. Biochim. Biophys. Acta 1850, 1059-1071 (2015).

[4] P.A. Janowski, C. Liu and D.A. Case. Molecular dynamics of triclinic lysozyme in a crystal lattice. Prot. Sci. 25, 87-102 (2016).

[5] A.H. Van Benschoten, L. Liu, A. Gonzalez, A.S. Brewster, N.K. Sauter, J.S. Fraser and M.E. Wall. Measuring and modeling diffuse scattering in protein X-ray crystallography. Proc. Natl. Acad. Sci. USA 113, 4069-4074 (2016).

[6] S.P. Meisburger and N. Ando. Correlated Motions from Crystallography beyond Diffraction. Acc. Chem. Res. 50, 580-583 (2017).

[7] K.A. Niessen, M. Xu, A. Paciaroni, A. Orecchini, E.H. Snell and A.G. Markelz. Moving in the right direction: Protein vibrational steering function. Biophys. J. 112, 933-942 (2017).

1. Computational Drug Design
2. Metalloenzymes
3. Molecular Dynamics
4. NMR