Case, David

	Phone:	732-445-5885
	E-mail:
	FAX:	732-445-5958
	Office:	Wright Rieman Labs 113
	Mail:	Chemistry & Chemical Biology, 610 Taylor Road, Piscataway, NJ 08854

Research Summary

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.

The Amber suite of biomolecular simulation programs

Prof. Case oversees development of the Amber suite of programs for biomolecular simulation. A large group of volunteers from many places (see photo) contributes to computer codes that are used in over 900 labs to carry out molecular dynamics analysis of proteins, carbohydrates and nucleic acids.

Simulations using Amber can be used to study many aspects of the structure and dynamics of biomolecules. Typical current research projects in the Case group include: the energetics of binding of drug candidates to enzymes; mechanical properties of nucleic acids; conformational preferences of polysaccharides; and the determination of solution structures by nuclear magnetic resonance (NMR). We are also active in the development of new energy functions (force fields) and simulation methods to help make these calculations more predictive.

See our web page, http://ambermd.org, for more information.

Analysis of nuclear magnetic resonance (NMR) spectra of biomolecules

Our overall goal is to extract the maximum amount of information about biomolecular structure and dynamics from NMR experiments. To this end, we are studying the use of direct refinement methods for determining biomolecular structures in solution, going beyond distance constraints to generate closer connections between calculated and observed spectra. We are also using quantum chemistry to study chemical shifts and spin-spin coupling constants. Other types of data, such as chemical shift anisotropies, direct dipolar couplings in partially oriented samples, and analysis of cross-correlated relaxation, are also being used to guide structure refinement. In recent structural studies, we focused on the binding of zinc finger proteins with RNA and on "abasic" DNA structures, where one of the nucleic acid bases is missing from a structure. The figure shows a recent result, from J. Chen, F.-Y. Dupradeau, D.A. Case, C.J. Turner and J. Stubbe. DNA oligonucleotides with A, T, G, or C opposite an abasic site: Structure and dynamics. Nucl. Acid Res. 36, 253-262 (2008).

Vibrational spectroscopy in proteins

A wide variety of proteins contain iron-sulfur clusters at their active sites; these proteins participate in electron-transport chains and in important enzymatic reactions such as the reduction of atmospheric nitrogen to ammonia by nitrogenase. Advances in synchrotron radiation sources now make it possible to probe the vibrational behavior of these clusters by using nuclear resonance vibrational spectroscopy (NRVS). This technique senses the coupling of a nuclear (Mossbauer) excitation to molecular vibrations. The result is a set of vibrational frequencies and intensities that indicate what sorts of deformations can take place. When the molecular structure is known, this information can contribute to the understanding of oxidation-reduction behavior and electron transfer kinetics. In situations in which the cluster structure is not known, NRVS data might useful as a “fingerprint” to help identify the structure.

We have been using quantum chemistry calculations to help understand NRVS spectra. Figure 1 shows a early example, comparing calculated and experimental spectra for a simple iron-sulfur “cubane” structure, a cluster type found in hundreds of known proteins. The calculations (shown as a dashed line) are in excellent agreement with experimental data (solid line), both in terms of frequencies and in terms of intensities. We are extending these calculations to models for the active site of nitrogenase, where the structure of the complex is still uncertain. If calculations like these can be used to closely track the experimental results, NRVS will be an important new tool for characterizing the active sites of metalloenzymes.

In extensions to this work, we are looking at more general aspects of vibrataional spectra and vibrational energy relaxation in proteins. The relevant experiments look at excitation of particular vibrations (such as C-D bonds that replace C-H bonds in proteins) and probe the "vibrational Stark effect" to analyze electric fields. For an example, see M.C. Thielges, D.A. Case and F.E. Romesberg. Carbon-deuterium bonds as probes of electrostatics in dihydrofolate reductase. J. Am. Chem. Soc. 130, 6597-6603 (2008).

Publications

T. Cramer, T. Steinbrecher, T. Koslowski, D.A. Case, F. Biscarini and F. Zerbetto. Water Induced Polaron Formation at the Pentacene Surface: Insights from QM-MM Simulations. Phys. Rev. B 79, 155316 (2009).

V. Wong, D.A. Case and A. Szabo. Influence of the coupling of interdomain and overall motions on NMR relaxation. Proc. Natl. Acad. Sci. USA 101, 11016-11021 (2009).

P.T. Lang, S.R. Brozell, S. Mukherjee, E.F. Pettersen, E.C. Meng, V. Thomas, R.C. Rizzo, D.A. Case, T.L. James and I.D. Kuntz. DOCK 6: Combining techniques to model RNAsmall molecule complexes. RNA 15, 1219-1230 (2009).

T. Hou, Z. Xu, W. Zhang, W. McLaughlin, D.A. Case, Y. Xu and W. Wang. Characterization of domain-peptide interaction interface: a unified model to decipher the binding specificity of SH3 domains. Mol. Cell. Proteomics 8, 639-649 (2009).

A.A. Fuller, D. Du, F. Liu, J.E. Davoren, G. Bhabha, G. Kroon, D.A. Case, H.J. Dyson, E.T. Powers, P. Wipf, M. Gruebele, and J.W. Kelly. Evaluation of beta-sheet folding nucleation kinetics by beta-turn mimics. Proc. Natl. Acad. Sci. USA 101, 11067-11072 (2009).

-----------------------------------------------------------------------------------------------------------------------

V. Wong and D.A. Case. Comparing MD simulations and NMR relaxation parameters. Annu. Rep. Comput. Chem. 4, 139-154 (2008).

T. Steinbrecher, T. Koslowski and D.A. Case. Direct simulation of electron transfer reactions in DNA radical cations. J. Phys. Chem. B 112, 16935-16944 (2008).

R.C. Walker, M.F. Crowley and D.A. Case. The implementation of a fast and accurate QM/MM potential method in Amber. J. Comput. Chem. 28, 1019-1031 (2008).

J. Chen, F.-Y. Dupradeau, D.A. Case, C.J. Turner and J. Stubbe. DNA oligonucleotides with A, T, G, or C opposite an abasic site: Structure and dynamics. Nucl. Acid Res. 36, 253-262 (2008).

Y. Guo, H. Wang, Y. Xiao, S. Vogt, R.K. Thauer, S. Shima, P.I. Volkers, T.B. Rauchfuss, V. Pelmentschikov, D.A. Case, E.E. Alp, W. Sturhahn, Y. Yoda, and S.P. Cramer. Characterization of the Fe Site in Methanothermobacter marburgensis Hydrogenase (mHmd) and a Model Compound via Nuclear Resonance Vibrational Spectroscopy (NRVS). Inorg. Chem. 47, 3969-3977 (2008).

V. Wong and D.A. Case. Evaluating rotational diffusion from protein MD simulations. J. Phys. Chem. B 112, 6013-6024 (2008).

A.P. Graves, D.M. Shivakumar, S.E. Boyce, M.P. Jacobson, D.A. Case and B. Shoichet. Rescoring docking hit lists for model cavity sites: predictions and experimental testing. J. Mol. Biol. 377, 914-934 (2008).

T. Hou, W. Zhang, D.A. Case, and W. Wang. Deciphering the binding patterns of the peptide ligands of amphiphysin-1 SH3 domain by analyzing the molecular interaction fields. J. Mol. Biol. 376, 1201-1214 (2008).

M.C. Thielges, D.A. Case and F.E. Romesberg. Carbon-deuterium bonds as probes of electrostatics in dihydrofolate reductase. J. Am. Chem. Soc. 130, 6597-6603 (2008).

V. Pelmenschikov, D.A. Case and L. Noodleman. Ligand-bound S = 1/2 FeMo-cofactor of nitrogenase: Hyperfine interaction analysis and implication for the central ligand X identity. Inorg. Chem. 47, 6162-6172 (2008).

Y. Bomble and D.A. Case. Multiscale modeling of nucleic acids: Insights into DNA flexibility. Biopolymers 89, 722-731 (2008).

J.A. Fee, D.A. Case and L. Noodleman. Toward a mechanism of proton pumping by the B-type cytochrome c oxidases: Application of density functional theory to cytochrome ba3 of Thermus thermophilus. J. Am. Chem. Soc., 130, 15002-15021 (2008).

------------------------------------------------------------------------------------------------

J. Mongan, C. Simmerling, J.A. McCammon, D.A. Case, and A. Onufriev. Generalized Born model with a simple, robust molecular volume correction. J. Chem. Theory Comput. 3, 156-169 (2007).

J. Chen, F.-Y. Dupradeau, D.A. Case, C.J. Turner and J. Stubbe. NMR structural studies and molecular modeling of duplex DNA containing normal and 4'-oxidized abasic sites. Biochemistry 46, 3096-3107 (2007).

R.K. Grover, S.J. Pond, Q. Cui, P. Subramaniam, M. Puga, D.A. Case, D.P. Millar and P. Wentworth, Jr. O-Glycoside orientation is an essential aspect of base J recognition by the kinetoplastid DNA-binding protein JBP1. Angew. Chemie 46, 2839-2843 (2007).

S. Moon and D.A. Case. A new model for chemical shifts of amide hydrogens in proteins. J. Biomol. NMR 38, 139-150 (2007).

G.M. Seabra, R.C. Walker, M. Elstner, D.A. Case, and A.E. Roitberg. Implementation of the SCC-DFTB method for hybrid QM/MM simulations within the Amber molecular dynamics package. J. Phys. Chem. A 111, 5655-5664 (2007).

S. Tang and D.A. Case. Vibrational averaging of chemical shift anisotropies in model peptides. J. Biomol. NMR 38, 255-266 (2007).

R.J. Payne, S. Ficht, S. Tang, A. Brik, Y.-Y. Yang, D.A. Case and C.-H Wong. Extended sugar-assisted glycopeptide ligations: Development, scope and application. J. Am. Chem. Soc. 129, 13527-13536 (2007).

D. Lukoyanov, V. Pelmenschikov, N. Maeser, M. Laryukhin, T.C. Yang, L. Noodleman, D.R. Dean, D.A. Case, L.C. Seefeldt, and B.M. Hoffman. Testing if the interstitial atom, X, of the nitrogenase molybdenum-iron cofactor is N or C: ENDOR, ESEEM, and DFT Studies of the S = 3/2 resting state in multiple environments. Inorg. Chem. 46, 11437-11449 (2007).

T. Steinbrecher, D.L. Mobley and D.A. Case. Non-linear scaling schemes for Lennard-Jones interactions in free energy calculation. J. Chem. Phys. 127, 214108 (2007).

L. Marinelli, S. Cosconati, T. Steinbrecher, V. Limongelli, A. Bertamino, E. Novellino, and D.A. Case. Homology modeling of NR2B modulatory momain of NMDA receptor and analysis of ifenprodil binding. Chem. Med. Chem. 2, 1498-1510 (2007).