Research Synopsis: Theoretical / Computational
Phone: (848) 445-5885
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).
P.A. Janowski, C. Liu and D.A. Case. Molecular dynamics of triclinic lysozyme in a crystal lattice. Prot. Sci. 25, 87-102 (2016).
I. Ivani, P.D. Dans, A. Noy, A. Pérez, I. Faustino, A. Hopsital, J. Walther, P. Andrió, R. Goñi, A. Balaceanu, G. Portella, F. Battistini, J.L. Gelpí, C. González, M. Vendruscolo, C.A. Laughton, S. Harris, D.A. Case and M. Orozco. Parmbsc1: A refined force field for DNA simulations. Nature Methods 13, 55-58 (2016).
J. Lee, X. Cheng, J. Swails, M.S. Yeom, P. Eastman, J. Lemkul, S. Wei, J. Buckner, J.C. Jeong, Y. Qi, S. Jo, V. Pande, D.A. Case, C.L. Brooks, III, A.D. MacKerell, Jr., J.B. Klauda and W. Im. CHARMM-GUI Input Generation for NAMD, GROMACS, AMBER, OpenMM, and CHARMM/OpenMM Simulations using the CHARMM Force Fields. J. Chem. Theory Comput. 12, 405-413 (2016).
H.T. Nguyen, S.A. Pabit, L. Pollack and D.A. Case. Extracting water and ion distributions from small angle X-ray scattering experiments. J. Chem. Phys. 144, 214105 (2016).
J. Johnson, D.A. Case, T. Yamazaki, S. Gusarov, A. Kovalenko and T. Luchko. Small Molecule Solvation Energy and Entropy from 3D-RISM. J. Phys. Cond. Mat. 28, 344002 (2016).
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)
G.M. Giambasu, D.M. York and D.A. Case. Structural fidelity and NMR relaxation analysis in a prototype RNA hairpin. RNA 21, 963-974 (2015).
W.J. Allen, T.E. Balius, S. Mukherjee, S.R. Brozell, D.T. Moustakas, P. T. Lang, D.A. Case, I.D. Kuntz, and R.C. Rizzo. DOCK 6: Impact of New Features and Current Docking Performance. J. Comput. Chem.36, 1132-1156 (2015).
S.C. Keane, X. Heng, K. Lu, S. Kharytonchyk, V. Ramakrishnan, G. Carter, S. Barton, A. Hosic, A. Florwick, J. Santos, N. Bolden, S. McCowin, D.A. Case, B. Johnson, M. Salemi, A. Telesnitsky, and M.F. Summers. Structure of the HIV-1 RNA packaging signal. Science, 348, 917-921 (2015).
A. Gutmanas, P.D. Adams, B. Bardiaux, H.M. Berman, D.A. Case, R.H. Fogh, P. Güntert, P.M.S. Hendrickx, T. Herrmann, G.J. Kleywegt, N. Kobayashi, O. Lange, J.L. Markley, G.T. Montelione, M. Nilges, T.J. Ragan, C.D. Schwieters, R. Tejero, E. Ulrich, S. Velankar, W.F. Vranken, J. Wedell, J. Westbrook, D.S. Wishart, and G.W. Vuister. NMR exchange format: a community-driven unified representation of NMR restraints data. Nature Struct. Mol. Biol. 22, 433-434 (2015).
G.M. Giambasu, M.K. Gebala, M.T. Panteva, D.A. Case, D. Herschlag and D.M. York. Competitive interaction of monovalent cations with DNA predicted by 3D-RISM. Nucl. Acids Res. 43, 8405-8415 (2015)
I. Fu, D.A. Case and J. Baum. Dynamic water-mediated hydrogen bonding in collagen model peptides. Biochemistry 54, 6029-6037(2015)..
J. Swails, T. Zhu, X. He and D.A. Case. AFNMR: Automated fragment quantum mechanical calculations of chemical shifts in biomolecules. J. Biomol. NMR 63, 125-139 (2015).
L. Salmon, G.M. Giambasu, E.N. Nikolova, K. Petzold, A. Bhattacharya, D.A. Case and H.M. Al-Hashimi. Modulating RNA Alignment Using Directional Dynamic Kinks: Application in Determining an Atomic-Resolution Ensemble for a Hairpin using NMR Residual Dipolar Couplings. J. Am. Chem. Soc. 137, 12954-12965 (2015).
G.M. Giambaşu, T. Luchko, D. Herschlag, D.M. York and D.A. Case. Ion counting from explicit solvent simulations and 3D-RISM. Biophys. J., 104, 883-894 (2014).
H. Nguyen, S.A. Pabitt, S. Meisburger, L. Pollack and D.A. Case. Accurate small and wide angle X-ray scattering profiles from atomic models of proteins and nucleic acids. J. Chem. Phys.114, 22D508 (2014).
D.S. Cerutti, W.C. Swope, J.E. Rice and D.A. Case. ff14ipq: A self-consistent force field for condensed-phase simulations of proteins. J. Chem. Theory Comput.10, 4515-4534 (2014).
M. Pasi, J.H. Maddocks, D. Beveridge, T.C. Bishop, D.A. Case, T. Cheatham III, B. Jayaram, F. Lankas, C. Laughton, J. Mitchel, R. Osman, M. Orozco, D. Petkeviciute, N. Spackova, J. Sponer, K. Zakrzewska and R. Lavery. microABC: a systematic microsecond molecular dynamics study of tetranucleotide sequence effects in B-DNA. Nucl. Acids Res.42, 12272-12283 (2014).
T.E. Cheatham, III and D.A. Case. Twenty-five years of nucleic acid simulations. Biopolymers, 99, 969-977 (2013).
X. Wu, S. Subramaniam, D.A. Case, K. Wu and B.R. Brooks. Map constrained self-guided Langevin dynamics. J. Struct. Biol.183, 429-440 (2013).
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).
D.A. Case. Chemical shifts in biomolecules. Curr. Opin. Struct. Biol.23, 172-176 (2013).
D.S. Cerutti, J.E. Rice, W. Swope, and D.A. Case. Derivation of fixed partial charges for amino acid analogs accommodating a specific water model and implicit polarization. J. Phys. Chem. B117, 2328-2338 (2013).
D. Mitra, S. George, J. Peters, S. Keable, V. Pelmenschikov, D.A. Case, and S.P. Cramer. Dynamics of the [4Fe-4S] cluster in Azotobacter vinelandii nitrogenase Fe protein in three core oxidation states via nuclear resonance vibrational spectroscopy (NRVS). J. Am. Chem. Soc. 135, 2530-2543 (2013).
I.S. Joung, T. Luchko and David A. Case. Simple electrolyte solutions: Comparison of RISM and molecular dynamics results for alkali halide solutions. J. Chem. Phys.138, 044103 (2013).
R. Salomon-Ferrer, D.A. Case and R.C. Walker. An overview of the Amber biomolecular simulation package. WIREs: Comput. Mol. Sci.,3, 198-210 (2013).
J. Latzer, T. Steinbrecher and D.A. Case. Revised AMBER parameters for bioorganic phosphates. J. Chem. Theory Comput.8, 4405-4412 (2012).
T. Luchko, I.S. Joung and D.A. Case. Integral equation theory of biomolecules and electrolytes. In Innovations in Biomolecular Modeling and Simulation, Volume 1. T. Schlick, ed. (London, Royal Society of Chemistry, 2012), pp. 51-86.
T. Steinbrecher, D.A. Case and A. Labahn. Free energy calculations on the binding of novel thiolactomycin derivatives to E. coli fatty acid synthase I. Bioorg. Med. Chem.20, 3446-3453 (2012).
S.R. Brozell, S. Mukherjee, T.E. Balius, D.R. Roe, D.A. Case and R.C. Rizzo. Evaluation of DOCK 6 as a pose generation and database enrichment tool. J. Comput. Aided Mol. Des.26, 749-773 (2012).
J.D. Kim, A. Godriguez-Ganillo, D.A. Case, V. Nanda and P.G. Falkowski. Energetic selection of topology in ferredoxins. PLoS Comput. Biol. 8, e1002463 (2012).
T. Luchko and D.A. Case. Implicit solvent models and electrostatics in molecular recognition. In: Protein-Ligand Interactions, H. Gohlke, ed. (Weinheim, Germany: Wiley-VCH, 2012), pp. 171-189.
J. Xia and D.A. Case. Sucrose in aqueous solution revisited. 1. Molecular dynamics simulations and direct and indirect dipolar coupling analysis. Biopolymers97, 276-288 (2012).
J. Xia and D.A. Case. Sucrose in aqueous solution revisited. 2. Adaptively biased molecular dynamics simulations and computational analysis of NMR relaxation. Biopolymers, 97, 289-302 (2012).
R. Chaudhuri, S. Tang, G. Zhao, H. Lu, D.A. Case and M.E. Johnson. Comparison of SARS and NL63 papain-Like protease binding sites and binding site dynamics: Inhibitor design implications. J. Mol. Biol. 414, 272-288 (2011).
J. Xia, C.J. Margulis and D.A. Case. Searching and optimizing structure ensembles for complex flexible sugars. J. Am. Chem. Soc.133, 15252-15255 (2011).
T. Gaillard and D.A. Case. Evaluation of DNA force fields in implicit solvation. J. Chem. Theory Comput.7, 3181-3198 (2011).
S. Tang and D.A. Case. Calculation of chemical shift anisotropy in proteins. J. Biomol. NMR51, 303-312 (2011).
I. Bertini, D.A. Case, L. Ferella, A. Giachetti and A. Rosato. A grid-enabled web portal for NMR structure refinement with AMBER. Bioinformatics, 27, 2384-2390 (2011).
T. Steinbrecher, I.S. Joung and D.A. Case. Soft-core potentials in thermodynamic integration: Comparing one- and two-step transformations. J. Comput. Chem.32, 3253-3263 (2011).
D. Mitra, V. Pelmenschikov, Y. Guo, D.A. Case, H. Wang, W. Dong, M. Tan, T. Ichiye, F. Jenney, Jr., M.W.W. Adams, M. Kaupp and S.P. Cramer. Dynamics of the [4Fe-4S] Cluster in Pyrococcus furiosus Ferredoxin via Nuclear Resonance Vibrational Spectroscopy (NRVS) and Resonance Raman Spectroscopy – Quantitative Simulation by Density Functional Theory. Biochemistry,50, 5220-5235 (2011).
V. Pelmenschikov, Y. Guo, H. Wang, S.P. Cramer and D.A. Case. Fe-H/D stretching and bending modes in nuclear resonant vibrational, Raman and infrared spectroscopies: Comparisons of density functional theory and experiment. Faraday Disc., 148, 409-420 (2011).
D.A. Case. In silico: An alternate approach to chemistry and biology. In Letters to a Young Chemist, A. Ghosh, ed. (New York: John Wiley & Sons, 2011), pp. 19-31.
R. Lavery, K. Zakrzewska, D. Beveridge, T.C. Bishop, D.A. Case, T. Cheatham, III, S. Dixit, B. Jayaram, F. Lankas, C. Laughton, J.H. Maddocks, A. Michon, R. Osman, M. Orozco, A. Perez, N. Spackova and J. Sponer. A systematic molecular dynamics study of nearest-neighbor effects on base pair and base pair step conformations and ﬂuctuations in B-DNA. Nucleic Acids Res. 38: 299-313 (2010).
D.S. Cerutti and D.A. Case. Multi-level Ewald: A scalable variant of traditional Ewald mesh methods. J. Chem. Theory Comput. 6, 443-459 (2010).
T. Luchko, S. Gusarov, D.R. Roe, C. Simmerling, D.A. Case, J. Tuszynski and A. Kovalenko. Three-dimensional molecular theory of solvation coupled with molecular dynamics in Amber. J. Chem. Theory Comput.6, 607-624 (2010).
B.S. Tolbert, Y. Miyazaki, S. Barton, B. Kinde, P. Starck, R. Singh, A. Bax, D.A. Case and M.F. Summers. Major groove width variations in RNA structures determined by NMR and impact of 13 C residual chemical shift anisotropy and 1 H-13 C residual dipolar coupling
on reﬁnement. J. Biomol. NMR47, 205-219 (2010).
K.F. Wong, F. Paesani, J.L. Sonnenberg, T. Yamamoto, J. Vanicek, W. Zhang, H.B. Schlegel, D.A. Case, T.E. Cheatham, III, W.H. Miller and G.A. Voth. Proton Transfer Studied Using a Reactive Potential Energy Surface Combined with Quantum Path Integrals. J. Chem. Theory Comput. 6, 2566-2580 (2010).
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. B114, 12811-12824 (2010).