The Computational Biophysics Section studies problems of biological significance using several theoretical techniques: molecular dynamics, molecular mechanics, modeling, ab initio analysis of small molecule structure, and molecular graphics. These techniques are applied to a wide variety of macromolecular systems.? ? Dr. Zheng's research aims to study the coupling between the global dynamics of a large protein complex and the local dynamics of its functional site (such as a ligand-binding site), we have introduced a structural deformation of the functional site (mimicking ligand-binding), and then computed the induced conformational changes of the whole protein. This calculation has two applications: first, predict ligand-binding induced inter-domain motions; second, obtain an effective Hamiltonian for the functional site residues by 'integrating out' the remaining degrees of freedom and then solve the local modes to describe the local dynamics of the functional site. For application, we have analyzed the coupling of dynamics between the nucleotide-binding site and the whole myosin/kinesin motor domains, which has shed light on the signaling pathway that transmits? the deformation at the nucleotide-binding site to the force-generating subdomains in these motor proteins.? ? Mr. O'Brien's research has focused on three primary areas (1) the early events in disease related protein aggregation, (2) the effect of denaturants and osmolytes on proteins and (3) the effect of confinement and protein sequence on the helix-coil transition. Computer simulations were previously used to study dimerization of a peptide fragment from the amyloidogenic Thransthyretin protein. The effects of sequence mutation, sequence shuffling, molecular confinement and crowding on this process were investigated. Mr. O'Brien has extended this project to investigate higher order aggregation events including 'tetramerization' (that is the aggregation of four peptide fragments) and the impact molecular crowding has on this process. Mr. O'Brien has also used simulations to ascertain the role protein sequence has in helix stability under cylindrical confinement in a carbon nanotube. The motivation for this project arose from the experimental observation that newly synthesized peptides form helicies or coils in the ribosome exit tunnel (which can be approximated as cylinder confinement) depending on sequence. Interestingly a diversity of behavior dependent on sequence was observed even for this simple case of carbon nanotube confinement.? ? Dr. Klauda?s research consists of collaborative work involving lipid structure and dynamics and independent work on substrate transport in a membrane protein. In collaboration with Prof. John Nagle (Carnegie Mellon University), molecular dynamics simulations are used to help experimentalists determine the structure of the liquid crystalline phase of lipids, specifically DMPC (1). This work has also resulted in a model-free method for determining membrane structures of pure and mixed lipid membranes. In addition to lipid structure, the rotational motion of lipids has been studied in collaboration with experimentalist, Prof. Alfred Redfield at Brandeis University and Prof. Mary Roberts at Boston College. Molecular dynamics simulations of the DPPC lipid bilayer have shown that a previously believed measure of lipid rotation is instead a combination of lipid wobble and rotation. Through this joint venture with experimentalists, we were able to determine the rotational and wobble diffusion constants of DPPC. Dr. Klauda has also discovered a finite size effect of lipid bilayer simulations in determining the lateral diffusion of lipids (2). Molecular dynamics simulations in small systems can result in artificially enhanced lipid diffusion. This finite size effect originates from the correlation length of lipid diffusion, which extends to next-nearest neighbors and propagates across the boundaries of a periodic box.? ? Dr. Klauda is also studying the transport of disaccharides in an important membrane protein of E. coli, lactose permease (LacY). Molecular dynamics simulations of LacY in an embedded lipid membrane have revealed that this protein has a greater affinity for the a-anomeric state of the sugar than b. The binding structure of these two sugars is different implying that experimental structures on a single sugar cannot be generalized to others. The binding of sugars also influences the protein structure such that b-disaccharides distort helix-4 to a greater extent than a-disaccharides.? ? Dr. Damjanovic's research focuses on study of the relationship between protein structure, dynamics and function. Due to a longer than microsecond timescale, the nature and pathways of conformational rearrangements in proteins are poorly understood. To tackle this problem, new methods that go beyond conventional molecular dynamics simulations need to be developed and benchmarked against experiments. We are using the recently developed, Self-Guided Langevin Dynamics simulation method, by Dr. Xiongwu Wu, to study conformational rearrangements induced by burial of charged groups in the protein interior. We are studying variants of staphylococcal nuclease in which an ionizable group is buried in the protein interior, in collaboration with Prof. Bertrand Garcia-Moreno (JHU) who is performing various biophysical experiments on these variants. SGLD simulations indicate changes in secondary structure that are not observable by conventional MD simulations and that are consistent with experimental findings. ? ? Dr. Stan's research focuses on chaperonin-mediated protein folding. We have used a bioinformatic approach to predict the natural substrate proteins for the Escherichia coli chaperonin GroEL based on two simple criteria. Natural substrate proteins should contain binding motifs similar in sequence to the mobile loop peptide of GroES that displaces the binding motif during the chaperonin cycle. Secondly, each substrate protein should contain multiple copies of the binding motif so that the chaperonin can perform ??work?? on the substrate protein. To validate these criteria, we have used a database of 252 proteins that have been experimentally shown to interact with the chaperonin machinery in vivo. More than 80% are identified by these criteria. The binding motifs of all 79 proteins in the database with a known three-dimensional structure are buried (<50% solvent-accessible surface area) in the native state. Our results show that the binding motifs are inaccessible in the native state but become solvent-exposed in unfolded state, thus enabling GroEL to distinguish between unfolded and native states.? ? Dr. Larkin's research involves the application of Quantum Mechanical/Molecular Modeling(QM/MM) and Molecular Dynamics simulation techniques to enzymatic reaction pathways. Specifically, Dr. Larkin is investigating reaction mechanisms of boronic acid inhibitors of Beta Lactamase enzymes that are responsible for increased resistance to penicillin antibiotics.? ? Dr. Che uses computing to explore fundamental problems in molecular recognition inspired by the biological world, and designs and develops innovate small molecules that are capable of imitate protein surfaces recognized by other macromolecules, transition states of enzymatic functions, and active sites of native enzymes.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Intramural Research (Z01)
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U.S. National Heart Lung and Blood Inst
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Lee, Juyong; Konc, Janez; Janeži?, Dušanka et al. (2017) Global organization of a binding site network gives insight into evolution and structure-function relationships of proteins. Sci Rep 7:11652
Damjanovic, Ana; Miller, Benjamin T; Schleif, Robert (2013) Understanding the basis of a class of paradoxical mutations in AraC through simulations. Proteins 81:490-8
Elegheert, Jonathan; Desfosses, Ambroise; Shkumatov, Alexander V et al. (2011) Extracellular complexes of the hematopoietic human and mouse CSF-1 receptor are driven by common assembly principles. Structure 19:1762-72
O'Brien, Edward P; Morrison, Greg; Brooks, Bernard R et al. (2009) How accurate are polymer models in the analysis of Forster resonance energy transfer experiments on proteins? J Chem Phys 130:124903
Klauda, Jeffery B; Roberts, Mary F; Redfield, Alfred G et al. (2008) Rotation of lipids in membranes: molecular dynamics simulation, 31P spin-lattice relaxation, and rigid-body dynamics. Biophys J 94:3074-83
Rosales, Tilman; Xu, Jianhua; Wu, Xiongwu et al. (2008) Molecular dynamics simulations of perylene and tetracene librations: comparison with femtosecond upconversion data. J Phys Chem A 112:5593-7
Woodcock, H Lee; Brooks, Bernard R; Pastor, Richard W (2008) Pathways and populations: stereoelectronic insights into the exocyclic torsion of 5-(hydroxymethyl)tetrahydropyran. J Am Chem Soc 130:6345-7
Lee, Yong-Sok; Pike, Victor W; Hodoscek, Milan (2008) Identification of the transition states in the inversion of 1,4-benzodiazepines with the ab initio replica path method. J Phys Chem A 112:1604-11
Klauda, Jeffery B; Eldho, Nadukkudy V; Gawrisch, Klaus et al. (2008) Collective and noncollective models of NMR relaxation in lipid vesicles and multilayers. J Phys Chem B 112:5924-9
Larkin, Joseph D; Bhat, Krishna L; Markham, George D et al. (2008) A computational characterization of boron-oxygen multiple bonding in HN=CH-CH=CH-NH-BO. J Phys Chem A 112:8446-54

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