http://www.ks.uiuc.edu/Publications/Papers/ This feed should track papers published by the TCB Group, primarily co-authored by Professor Klaus Schulten. en Copyright 1994-2007, TCB Group @ UIUC webmaster@ks.uiuc.edu <p class='bib'> <b> Ilia A. Solov'yov, Danielle Chandler, and Klaus Schulten. Exploring the possibilities for radical pair effects in cryptochrome. <em>Plant Signaling and Behavior</em>, 2008. In press. </b> </p> <p class='abstract'> The ability of some animals to sense magnetic fields has long captured the human imagination. In our recent paper, we explored how radical pair effects in the protein cryptochrome may underlie the magnetic orientation sense of migratory birds. Here we explain our model and discuss its relationship to experimental results on plant cryptochromes, as well as discuss the next steps in refining our model, and explore alternate but related possibilities for modeling and understanding cryptochrome as a magnetic sensor. </p> <p class='request'> <a href='http://www.ks.uiuc.edu/Publications/Papers/request.cgi?tbcode=SOLO2008'>Full Text</a> </p> http://www.ks.uiuc.edu/Publications/Papers/paper.cgi?tbcode=SOLO2008 <p class='bib'> <b> Zhongzhou Chen, Jizhong Lou, Cheng Zhu, and Klaus Schulten. Flow induced structural transition in the β-switch region of glycoprotein Ib. <em>Biophysical Journal</em>, 2008. In press. </b> </p> <p class='abstract'> The impact of fluid flow on structure and dynamics of biomolecules has recently gained much attention. In this paper we present a molecular dynamics algorithm that serves to generate stable water flow under constant temperature, for the study of flow-induced protein behavior. Flow simulations were performed on the 16-residue <IMG WIDTH="13" HEIGHT="30" ALIGN="MIDDLE" BORDER="0" SRC="/Publications/Papers/abstracts/CHEN2008/img1.png" ALT="$\beta$">-switch region of platelet glycoprotein Ib<IMG WIDTH="13" HEIGHT="13" ALIGN="BOTTOM" BORDER="0" SRC="/Publications/Papers/abstracts/CHEN2008/img2.png" ALT="$\alpha$">, for which crystal structures of its N-terminal domain alone and in complex with the A1 domain of von Willebrand factor have been solved. Comparison of the two structures reveals a conformational change in this region, which, upon complex formation, switches from an unstructured loop to a <IMG WIDTH="13" HEIGHT="30" ALIGN="MIDDLE" BORDER="0" SRC="/Publications/Papers/abstracts/CHEN2008/img1.png" ALT="$\beta$">-hairpin. Interaction between glycoprotein Ib and von Willebrand factor initiates platelet adhesion to injured vessel walls, and the adhesion is enhanced by blood flow. It has been hypothesized that the loop to <IMG WIDTH="13" HEIGHT="30" ALIGN="MIDDLE" BORDER="0" SRC="/Publications/Papers/abstracts/CHEN2008/img1.png" ALT="$\beta$">-hairpin transition in glycoprotein Ib<IMG WIDTH="13" HEIGHT="13" ALIGN="BOTTOM" BORDER="0" SRC="/Publications/Papers/abstracts/CHEN2008/img2.png" ALT="$\alpha$"> is induced by flow before binding to von Willebrand factor. The simulations revealed clearly a flow-induced loop <IMG WIDTH="19" HEIGHT="15" ALIGN="BOTTOM" BORDER="0" SRC="/Publications/Papers/abstracts/CHEN2008/img3.png" ALT="$\rightarrow$"> <IMG WIDTH="13" HEIGHT="30" ALIGN="MIDDLE" BORDER="0" SRC="/Publications/Papers/abstracts/CHEN2008/img1.png" ALT="$\beta$">-hairpin transition. The transition is dominated by the entropy of the protein, and is seen to occur in two steps, namely a dihedral rotation step followed by a side group packing step. <P> </p> <p class='request'> <a href='http://www.ks.uiuc.edu/Publications/Papers/request.cgi?tbcode=CHEN2008'>Full Text</a> </p> http://www.ks.uiuc.edu/Publications/Papers/paper.cgi?tbcode=CHEN2008 <p class='bib'> <b> Leonardo G. Trabuco, Elizabeth Villa, Kakoli Mitra, Joachim Frank, and Klaus Schulten. Flexible fitting of atomic structures into electron microscopy maps using molecular dynamics. <em>Structure</em>, 16:673-683, 2008. </b> </p> <p class='abstract'> A novel method to flexibly fit atomic structures into electron microscopy (EM) maps using molecular dynamics simulations is presented. The simulations incorporate the EM data as an external potential added to the molecular dynamics force field, allowing all internal features present in the EM map to be used in the fitting process, while the model remains fully flexible and stereochemically correct. The molecular dynamics flexible fitting (MDFF) method is validated for available crystal structures of protein and RNA in different conformations; measures to assess and monitor the fitting process are introduced. The MDFF method is then used to obtain high-resolution structures of the <I>E. coli</I> ribosome in different functional states imaged by cryo-EM. </p> <p class='request'> <a href='http://www.ks.uiuc.edu/Publications/Papers/request.cgi?tbcode=TRAB2008'>Full Text</a> </p> http://www.ks.uiuc.edu/Publications/Papers/paper.cgi?tbcode=TRAB2008 <p class='bib'> <b> Amy Y. Shih, Stephen G. Sligar, and Klaus Schulten. Molecular models need to be tested: the case of a solar flares discoidal HDL model. <em>Biophysical Journal</em>, 2008. In press. </b> </p> <p class='abstract'> In the absence of atomic structures of high-density lipoproteins in their lipid bound states, many molecular models have been produced based on experimental data. Using molecular dynamics, we show that a recently proposed ``solar flare'' model of discoidal high-density lipoprotein is implausible. Our simulations show a collapse of the protruding solar flare loops and a notable protein rearrangement due to an energetically unfavorable orientation of the hydrophobic protein surface towards the aqueous solvent. </p> <p class='request'> <a href='http://www.ks.uiuc.edu/Publications/Papers/request.cgi?tbcode=SHIH2008A'>Full Text</a> </p> http://www.ks.uiuc.edu/Publications/Papers/paper.cgi?tbcode=SHIH2008A <p class='bib'> <b> Melih K. Sener and Klaus Schulten. From atomic-level structure to supramolecular organization in the photosynthetic unit of purple bacteria. In C. Neil Hunter, Fevzi Daldal, Marion C. Thurnauer, and J. Thomas Beatty, editors, <em>The Purple Phototrophic Bacteria</em>, chapter 16. Springer, 2008. In press. </b> </p> <p class='abstract'> The purple bacterial photosynthetic unit (PSU) is a macromolecular assembly of remarkable simplicity that harvests sunlight with the cooperation of only half a dozen different kinds of proteins. This chapter provides a summary of recent research on the architectural and biophysical aspects of the PSU and its constituents. First, a brief overview is provided of the structure of light-harvesting components. Then the effects of thermal disorder and spectral universality on the light-harvesting function of the pigment-protein complexes is discussed, followed by an account of the physical constraints that shape the evolution of light-harvesting complexes in general. Finally, a summary is provided of recent research on the in silico assembly of an entire PSU in atomic detail. This supramolecular reconstruction of the PSU is made possible by the recent availability of not only the structural data on the individual constituent proteins but also on their global arrangement. The reconstruction is performed by seamlessly combining data from X-ray crystallography, NMR, cryo-electron microscopy, and atomic force microscopy using computational modeling. The architecture of the PSU vesicle that emerges constitutes nearly two hundred light-harvesting proteins, containing around four thousand chlorophylls, which act cooperatively to maintain a very high quantum yield in a pigment array distributed over a pseudo-spherical intracytoplasmic membrane domain with an inner diameter of 60 nm. </p> <p class='request'> <a href='http://www.ks.uiuc.edu/Publications/Papers/request.cgi?tbcode=SENE2008'>Full Text</a> </p> http://www.ks.uiuc.edu/Publications/Papers/paper.cgi?tbcode=SENE2008 <p class='bib'> <b> Basak Isin, Klaus Schulten, Emad Tajkhorshid, and Ivet Bahar. Mechanism of signal propagation upon retinal isomerization: Insights from molecular dynamics simulations of rhodopsin restrained by normal modes. <em>Biophysical Journal</em>, 2008. In press. </b> </p> <p class='abstract'> As the only structurally resolved member of the pharmaceutically relevant family of G-protein-coupled receptors (GPCRs), rhodopsin serves as a prototype for understanding the mechanism of GPCR activation. Here, we aim at exploring functionally relevant conformational changes and signal transmission mechanisms involved in its photoactivation. To this aim, we propose a molecular dynamics simulation protocol that utilizes normal modes derived from anisotropic network model. Deformations along multiple low frequency modes of motion are used to efficiently sample collective conformational changes in the presence of explicit membrane and water environment, in consistency with inter-residue interactions indicated by experimental data. We identified two highly stable regions, one clustered near the chromophore, and the other near the cytoplasmic ends of transmembrane helices H1, H2, and H7. Due to redistribution of interactions in the neighborhood of the chromophore upon stabilization of the trans form, local structural rearrangements in the adjoining H3-H6 residues are efficiently propagated to the cytoplasmic end of these particular helices. In the proposed activated state, all-trans-retinal interacts with Cys167 on H4 and Phe203 on H5, which were not accessible in the dark state, and exhibits stronger interactions with H5, while some of the contacts made (in the cis-form) with H6 are lost. </p> <p class='request'> <a href='http://www.ks.uiuc.edu/Publications/Papers/request.cgi?tbcode=ISIN2008'>Full Text</a> </p> http://www.ks.uiuc.edu/Publications/Papers/paper.cgi?tbcode=ISIN2008 <p class='bib'> <b> Peter L. Freddolino, Feng Liu, Martin Gruebele, and Klaus Schulten. Ten-microsecond MD simulation of a fast-folding WW domain. <em>Biophysical Journal</em>, 94:L75-L77, 2008. </b> </p> <p class='abstract'> All-atom molecular dynamics (MD) simulations of protein folding allow analysis of the folding process at an unprecedented level of detail. Unfortunately, such simulations have not yet reached their full potential both due to difficulties in sufficiently sampling the microsecond timescales needed for folding, and because the force field used may yield neither the correct dynamical sequence of events nor the folded structure. The ongoing study of protein folding through computational methods thus requires both improvements in the performance of molecular dynamics programs to make longer timescales accessible, and testing of force fields in the context of folding simulations. We report a ten-microsecond simulation of an incipient downhill-folding WW domain mutant along with measurement of a molecular time and activated folding time of 1.5 microseconds and 13.3 microseconds, respectively. The protein simulated in explicit solvent exhibits several metastable states with incorrect topology and does not assume the native state during the present simulations. </p> <p class='request'> <a href='http://www.ks.uiuc.edu/Publications/Papers/request.cgi?tbcode=FRED2008A'>Full Text</a> </p> http://www.ks.uiuc.edu/Publications/Papers/paper.cgi?tbcode=FRED2008A <p class='bib'> <b> Christopher I. Rodrigues, David J. Hardy, John E. Stone, Klaus Schulten, and Wen-Mei W. Hwu. GPU acceleration of cutoff pair potentials for molecular modeling applications. <em>Proceedings of the 2008 Conference On Computing Frontiers</em>, 2008. In press. </b> </p> <p class='abstract'> The advent of systems biology requires the simulation of ever-larger biomolecular systems, demanding a commensurate growth in computational power. This paper examines the use of the NVIDIA Tesla C870 graphics card programmed through the CUDA toolkit to accelerate the calculation of cutoff pair potentials, one of the most prevalent computations required by many different molecular modeling applications. We present algorithms to calculate electrostatic potential maps for cutoff pair potentials. Whereas a straightforward approach for decomposing atom data leads to low compute efficiency, a newer strategy enables fine-grained spatial decomposition of atom data that maps efficiently to the C870's memory system while increasing work-efficiency of atom data traversal by a factor of 5. The memory addressing flexibility exposed through CUDA's SPMD programming model is crucial in enabling this new strategy. An implementation of the new algorithm provides a greater than threefold performance improvement over our previously published implementation and runs 12 to 20 times faster than optimized CPU-only code. The lessons learned are generally applicable to algorithms accelerated by uniform grid spatial decomposition. </p> <p class='request'> <a href='http://www.ks.uiuc.edu/Publications/Papers/request.cgi?tbcode=RODR2008'>Full Text</a> </p> http://www.ks.uiuc.edu/Publications/Papers/paper.cgi?tbcode=RODR2008 <p class='bib'> <b> Marcos Sotomayor and Klaus Schulten. The allosteric role of the Ca<sup>++</sup> switch in adhesion and elasticity of C-cadherin. <em>Biophysical Journal</em>, 2008. In press. </b> </p> <p class='abstract'> Modular proteins such as titin, fibronectin, and cadherin are ubiquitous components of living cells. Often involved in signaling and mechanical processes, their architecture is characterized by domains containing a variable number of heterogeneous ``repeats'' arranged in series, with either flexible or rigid linker regions that determine their elasticity. Cadherin repeats arranged in series are unique in that linker regions also feature calcium binding motifs. While it is well known that the extracellular repeats of cadherin proteins mediate cell-cell adhesion in a calcium-dependent manner, the molecular mechanisms behind the influence of calcium in adhesion dynamics and cadherin's mechanical response are not well understood. Here we show, using molecular dynamics simulations, how calcium ions control the structural integrity of cadherin's linker regions, thereby affecting cadherin's equilibrium dynamics, the availability of key residues involved in cell-cell adhesion, and cadherin's mechanical response. The all-atom, multi-nanosecond molecular dynamics simulations involved the entire C-cadherin extracellular domain solvated in water (a 345,000 atom system). Equilibrium simulations show that the extracellular domain maintains its crystal conformation (elongated and slightly curved) when calcium ions are present. In the absence of calcium ions, however, it assumes a disordered conformation. The conserved residue Trp<IMG WIDTH="10" HEIGHT="18" ALIGN="BOTTOM" BORDER="0" SRC="/Publications/Papers/abstracts/SOTO2008/img1.png" ALT="$^2$">, which is thought to insert itself into a hydrophobic pocket of another cadherin molecule (thereby providing the basis for cell-cell adhesion) switches conformation from exposed to intermittently buried upon removal of calcium ions. Furthermore, the overall mechanical response of C-cadherin's extracellular domain is characterized at low force by changes in shape (tertiary structure elasticity), and at high force by unraveling of secondary structure elements (secondary structure elasticity). This mechanical response is modulated by calcium ions at both low and high force, switching from a stiff, rod-like to a soft, entropic-like behavior upon removal of ions. The simulations provide an unprecedented molecular view of calcium mediated allostery in cadherins, also illustrating the general principles of linker mediated elasticity of modular proteins relevant for cell-cell adhesion and sound transduction, but also muscle elasticity. </p> <p class='request'> <a href='http://www.ks.uiuc.edu/Publications/Papers/request.cgi?tbcode=SOTO2008'>Full Text</a> </p> http://www.ks.uiuc.edu/Publications/Papers/paper.cgi?tbcode=SOTO2008 <p class='bib'> <b> Aruna Rajan, Michael S. Strano, Daniel A. Heller, Tobias Hertel, and Klaus Schulten. Length dependent optical effects in single walled carbon nanotubes. <em>Journal of Physical Chemistry B</em>, 2008. In press. </b> </p> <p class='abstract'> Recently, Heller et al. reported length dependent effects on the relative photoluminescence (PL) quantum yield of single walled carbon nanotubes (SWNTs). We propose a simple model involving thermal diffusion of excitons along the nanotube axis and quenching at the ends, to explain the observed trend in their data. By fitting to our model, we extract a diffusion coefficient of 6 cm<IMG WIDTH="10" HEIGHT="18" ALIGN="BOTTOM" BORDER="0" SRC="/Publications/Papers/abstracts/RAJA2008/img1.png" ALT="$^{2}$">/sec for excitons in SWNTs. Assuming a mono exponential decay of exciton photoluminescence, we also predict that effective length dependent PL lifetimes for these excitons lie in the range of 1 ps to 27 ps. Experimental observations are shown to be consistent with stochastic rather than wavepacket like exciton migration, which is in agreement with ultrafast excitonic dephasing. Edge effects seem to limit the use of short SWNTs as optical sensors. </p> <p class='request'> <a href='http://www.ks.uiuc.edu/Publications/Papers/request.cgi?tbcode=RAJA2008'>Full Text</a> </p> http://www.ks.uiuc.edu/Publications/Papers/paper.cgi?tbcode=RAJA2008 <p class='bib'> <b> Bernard Lim, Eric H. Lee, Marcos Sotomayor, and Klaus Schulten. Molecular basis of fibrin clot elasticity. <em>Structure</em>, 16:449-459, 2008. </b> </p> <p class='abstract'> Blood clots must be mechanically stable to stop hemorrhage, yet elastic enough to buffer blood’s shear forces. Upsetting this balance can result in clot rupture, leading to lifethreatening thromboembolic disease including stroke, pulmonary embolism and heart attacks. With the global rise in obesity (a condition associated with cardiovascular disease) and atrial fibrillation (a disorder of heart rhythm characterized by irregularity) in world populations, cardiothromboembolic disease has reached epidemic proportions, creating an urgent need to understand and control the mechanisms that govern blood clot elasticity. Fibrin, the main component of a haemostatic plug, or blood clot, is formed from molecules of fibrinogen activated by thrombin. Although it is well known that fibrin possesses considerable elasticity, the molecular basis of this elasticity is unknown. Here we use atomic force microscopy (AFM) to probe the mechanical properties of single molecules of fibrinogen and fibrin protofibrils. The results show that the mechanical unfolding of the coiled <IMG WIDTH="13" HEIGHT="13" ALIGN="BOTTOM" BORDER="0" SRC="/Publications/Papers/abstracts/LIM2008/img1.png" ALT="$\alpha$">-helices (commonly known as ‘coiled-coils’) of single fibrinogen molecules and also fibrin protofibrils is characterized by a distinctive force plateau (an intermediate transition state which has been related to elasticity) in the force-extension curve. Steered molecular dynamics (SMD) simulations of single fibrinogen molecule stretching agree closely with the AFM results and relate the plateau force to a detailed stepwise unfolding of fibrinogen’s coiled <IMG WIDTH="13" HEIGHT="13" ALIGN="BOTTOM" BORDER="0" SRC="/Publications/Papers/abstracts/LIM2008/img1.png" ALT="$\alpha$">-helices and also its central domain. AFM data also show that varying pH and calcium ion concentrations alters the mechanical resilience of fibrinogen. This study provides the first direct evidence for the coiled <IMG WIDTH="13" HEIGHT="13" ALIGN="BOTTOM" BORDER="0" SRC="/Publications/Papers/abstracts/LIM2008/img1.png" ALT="$\alpha$">-helices of fibrinogen as a source of fibrin elasticity and opens the way for future therapies that modulate the elasticity of blood clots, thereby potentially altering the risk for thromboembolic disease. </p> <p class='request'> <a href='http://www.ks.uiuc.edu/Publications/Papers/request.cgi?tbcode=LIM2008'>Full Text</a> </p> http://www.ks.uiuc.edu/Publications/Papers/paper.cgi?tbcode=LIM2008 <p class='bib'> <b> Christophe Chipot and Klaus Schulten. Understanding structure and function of membrane proteins using free energy calculations. In Eva Pebay-Peyroula, editor, <em>Biophysical analysis of membrane proteins. Investigating structure and function</em>, pp. 187-211. Wiley, Weinheim, 2008. </b> </p> <p class='abstract'> </p> <p class='request'> <a href='http://www.ks.uiuc.edu/Publications/Papers/request.cgi?tbcode=CHIP2008'>Full Text</a> </p> http://www.ks.uiuc.edu/Publications/Papers/paper.cgi?tbcode=CHIP2008 <p class='bib'> <b> Valeria Vasquez, Marcos Sotomayor, D. Marien Cortes, Benoit Roux, Klaus Schulten, and Eduardo Perozo. Three dimensional architecture of membrane-embedded MscS in the closed conformation. <em>Journal of Molecular Biology</em>, 378:55-70, 2008. </b> </p> <p class='abstract'> The mechanosensitive channel of small conductance (MscS) is part of a coordinated response to osmotic challenges in E. coli. MscS opens as a result of membrane tension changes, thereby releasing small solutes and effectively acting as an osmotic safety valve. Both, the functional state depicted by its crystal structure and its gating mechanism remain unclear. Here, we combine site-directed spin labeling, electron paramagnetic resonance (EPR) spectroscopy, and molecular dynamics simulations with novel energy restraints based on experimental EPR data to investigate the native transmembrane and periplasmic molecular architecture of closed MscS in a lipid bilayer. In the closed conformation, MscS shows a more compact transmembrane domain than in the crystal structure, characterized by a realignment of the transmembrane segments towards the normal of the membrane. The previously unresolved NH2-terminus forms a short helical hairpin capping the extracellular ends of TM1 and TM2 and in close interaction with the bilayer surface. The present three-dimensional model of membrane-embedded MscS in the closed state represents a key step in determining the molecular mechanism of MscS gating. </p> <p class='request'> <a href='http://www.ks.uiuc.edu/Publications/Papers/request.cgi?tbcode=VASQ2008'>Full Text</a> </p> http://www.ks.uiuc.edu/Publications/Papers/paper.cgi?tbcode=VASQ2008 <p class='bib'> <b> Amy Y. Shih, Peter L. Freddolino, Anton Arkhipov, Stephen G. Sligar, and Klaus Schulten. Molecular modeling of the structural properties and formation of high-density lipoprotein particles. In Scott Feller, editor, <em>Current Topics in Membranes: Computational Modeling of Membrane Bilayers</em>. Elsevier, 2008. In press. </b> </p> <p class='abstract'> Even though high density lipoproteins (HDL) have been studied for decades, and implications of HDL for coronary heart disease are well documented, the structure of apo A-I and the transitions from lipid-free/poor to nascent discoidal to mature spherical HDL particles are not well characterized. The large structural changes in HDL particles along with the plasticity of the apo A-I protein have been difficult to study by traditional experimental high-resolution structural techniques such as X-ray crystallography and NMR. Any structure arising from such techniques would be static by nature and would not reveal in a dynamical sense the assembly and transformations of HDL particles. Molecular dynamics simulations, on the other hand, allow one to image the dynamic assembly and transformation of HDL. In this review, the simulation methods used to simulate lipoprotein particles, namely all-atom and coarse-grained molecular dynamics, will be introduced along with small-angle X-ray scattering, an experimental method that resolves the shape HDL particles. Recent progress towards determining computationally and experimentally structure and assembly of discoidal HDL and idealized nanodisc particles will then be presented. <BR><HR> </p> <p class='request'> <a href='http://www.ks.uiuc.edu/Publications/Papers/request.cgi?tbcode=SHIH2008'>Full Text</a> </p> http://www.ks.uiuc.edu/Publications/Papers/paper.cgi?tbcode=SHIH2008 <p class='bib'> <b> Peter L. Freddolino, Anton Arkhipov, Amy Y. Shih, Ying Yin, Zhongzhou Chen, and Klaus Schulten. Application of residue-based and shape-based coarse graining to biomolecular simulations. In Gregory A. Voth, editor, <em>Coarse-Graining of Condensed Phase and Biomolecular Systems</em>. Chapman and Hall/CRC Press, Taylor and Francis Group, 2008. In press. </b> </p> <p class='abstract'> A wide variety of coarse-graining methods for biological systems currently exist, ranging in some sense from united-atom models to elastic network models. We focus on the principles and applications of two classes of biological coarse-graining, namely residue-based and shape-based coarse graining. Residue-based CG is a broad family of methods in which clusters of 10-20 covalently bonded atoms are represented by one bead; it is a fairly natural and common method for coarse-graining when a speedup of 1-2 orders of magnitude over all-atom simulations is required. Shape-based CG is a method recently developed in our group which uses a neural network algorithm to assign CG beads to domains of a protein, efficiently reproducing the shape of the protein with a minimal number of particles. Interactions between beads are then parameterized from all-atom simulations of the bead components. In this chapter we present a summary of both methods, along with exemplary applications of residue-based CG to two lipid-protein systems involving large-scale conformational changes, and of shape-based CG to the mechanical properties of polymeric systems. </p> <p class='request'> <a href='http://www.ks.uiuc.edu/Publications/Papers/request.cgi?tbcode=FRED2008'>Full Text</a> </p> http://www.ks.uiuc.edu/Publications/Papers/paper.cgi?tbcode=FRED2008 <p class='bib'> <b> Jordi Cohen, Kenneth W. Olsen, and Klaus Schulten. Finding gas migration pathways in proteins using implicit ligand sampling. In Robert K. Poole, editor, <em>Globins and other NO-reactive Proteins in Microbes, Plants and Invertebrates</em>, volume 437 of <em>Methods in Enzymology</em>, pp. 437-455. Elsevier, 2008. </b> </p> <p class='abstract'> Implicit ligand sampling is a practical, efficient and accurate method for finding the gas migration pathways for small hydrophobic gas molecules such as oxygen inside proteins. The method infers the gas migration pathways by calculating the potential of mean force for the gas molecule everywhere inside the protein by means of a molecular dynamics simulation of the protein in the absence of the gas molecule. Pathways can be constructed by connecting the areas of the protein which are favorable to the presence of gas. This method has the advantage of providing a comprehensive overview of all possible gas migration pathways and barriers in a given protein from a single simulation run. Implicit ligand sampling has been applied to a large number of hemoproteins. The example of the truncated hemoglobin from <I>Paramecium caudatum</I> is given to illustrate the method. </p> <p class='request'> <a href='http://www.ks.uiuc.edu/Publications/Papers/request.cgi?tbcode=COHE2008'>Full Text</a> </p> http://www.ks.uiuc.edu/Publications/Papers/paper.cgi?tbcode=COHE2008 <p class='bib'> <b> Klaus Schulten, James C. Phillips, Laxmikant V. Kalé, and Abhinav Bhatele. Biomolecular modeling in the era of petascale computing. In David Bader, editor, <em>Petascale Computing: Algorithms and Applications</em>, pp. 165-181. Chapman and Hall/CRC Press, Taylor and Francis Group, New York, 2008. </b> </p> <p class='abstract'> Each time step in a biomolecular simulation is small, yet we need many million of them to simulate a small interval of time in the life of a biomolecule. Therefore, one has to aggressively parallelize a small computation with high parallel efficiency. The NAMD design is based on the concept of Charm++ migratable objects and is fundamentally adequate to scale to petascale machines--this is indicated by the 1-2 milliseconds time per step achieved by NAMD for some benchmarks, with ratio of atoms to processor in a similar range that we expect to see on petascale machines. We have demonstrated scalability to machines with tens of thousands of processors on biomolecular simulations of scientific importance. Implementation strategies have been reworked to eliminate obstacles to petascale through memory footprint reduction and fine grained decomposition of the PME computation. All this has made the study of large molecules such as the ribosome and entire viruses possible today and will enable even larger and longer simulations on future machines. </p> <p class='request'> <a href='http://www.ks.uiuc.edu/Publications/Papers/request.cgi?tbcode=SCHU2008'>Full Text</a> </p> http://www.ks.uiuc.edu/Publications/Papers/paper.cgi?tbcode=SCHU2008 <p class='bib'> <b> Jerome Henin, Emad Tajkhorshid, Klaus Schulten, and Christophe Chipot. Diffusion of glycerol through <i>Escherichia coli</i> aquaglyceroporin GlpF. <em>Biophysical Journal</em>, 94:832-839, 2008. </b> </p> <p class='abstract'> The glycerol uptake facilitator, GlpF, a major intrinsic protein found in Escherichia coli, conducts selectively water and glycerol across the inner membrane. The free energy landscape characterizing the assisted transport of glycerol by this homotetrameric aquaglyceroporin has been explored by means of equilibrium molecular dynamics over a time scale spanning 0.12<IMG WIDTH="13" HEIGHT="29" ALIGN="MIDDLE" BORDER="0" SRC="/Publications/Papers/abstracts/HENI2008/img1.png" ALT="$\mu$">s. In order to overcome the free energy barriers of the conduction pathway, an adaptive biasing force (ABF) is applied to the glycerol molecule confined in each of the four channels. The results illuminate the critical role played by intramolecular relaxation on the diffusion properties of the permeant. The present free energy calculations reveal that glycerol tumbles and isomerizes on a time scale comparable to that spanned by its ABF-assisted conduction in GlpF. As a result, reorientation and conformational equilibrium of glycerol in GlpF constitute a bottleneck in the molecular simulations of the permeation event. A profile characterizing the position-dependent diffusion of the permeant has been determined, allowing reaction rate theory to be applied for investigating conduction kinetics based on the measured free energy landscape. </p> <p class='request'> <a href='http://www.ks.uiuc.edu/Publications/Papers/request.cgi?tbcode=HENI2008'>Full Text</a> </p> http://www.ks.uiuc.edu/Publications/Papers/paper.cgi?tbcode=HENI2008 <p class='bib'> <b> Aleksei Aksimentiev, Robert Brunner, Jordi Cohen, Jeffrey Comer, Eduardo Cruz-Chu, David Hardy, Aruna Rajan, Amy Shih, Grigori Sigalov, Ying Yin, and Klaus Schulten. Computer modeling in biotechnology, a partner in development. In <em>Protocols in Nanostructure Design</em>, Methods in Molecular Biology. Humana Press, 2008. In press. </b> </p> <p class='abstract'> Computational modeling can be a useful partner in biotechnology, in particular, in nanodevice engineering. Such modeling guides development through nanoscale views of biomolecules and devices not available through experimental imaging methods. We illustrate the role of computational modeling, mainly of molecular dynamics, through four case studies: development of silicon bionanodevices for single molecule electrical recording, development of carbon nanotube-biomolecular systems as in vivo sensors, development of lipoprotein nanodiscs for assays of single membrane proteins, and engineering of oxygen tolerance into the enzyme hydrogenase for photosynthetic hydrogen gas production. The four case studies show how molecular dynamics approaches were adapted to the specific technical uses through (i) multi-scale extensions, (ii) fast quantum chemical force field evaluation, (iii) coarse graining, and (iv) novel sampling methods. The adapted molecular dynamics simulations provided key information on device behavior and revealed development opportunities, arguing that the "computational microscope" is an indispensable nanoengineering tool. </p> <p class='request'> <a href='http://www.ks.uiuc.edu/Publications/Papers/request.cgi?tbcode=AKSI2008'>Full Text</a> </p> http://www.ks.uiuc.edu/Publications/Papers/paper.cgi?tbcode=AKSI2008 <p class='bib'> <b> Michelle Gower, Jordi Cohen, James Phillips, Richard Kufrin, and Klaus Schulten. Managing biomolecular simulations in a grid environment with NAMD-G. In <em>Proceedings of the 2006 TeraGrid Conference</em>, 2006. (7 pages). </b> </p> <p class='abstract'> Experiences designing and deploying NAMD-G, an infrastructure for executing biomolecular simulations using the parallel molecular dynamics code NAMD within the context of a Computational Grid, are described. The effort is motivated by a general outline of the tasks involved in conducting research of this class as traditionally undertaken, followed by a description of the enhancements offered by current developments in Grid technologies. Specifics of the initial implementation of NAMD-G are given and a brief example of the use of the system in real-world scientific investigations simulating gas permeation in proteins is provided. </p> <p class='request'> <a href='http://www.ks.uiuc.edu/Publications/Papers/request.cgi?tbcode=GOWE2006'>Full Text</a> </p> http://www.ks.uiuc.edu/Publications/Papers/paper.cgi?tbcode=GOWE2006 <p class='bib'> <b> Melih K. Sener, John D. Olsen, C. Neil Hunter, and Klaus Schulten. Atomic level structural and functional model of a bacterial photosynthetic membrane vesicle. <em>Proceedings of the National Academy of Sciences, USA</em>, 104:15723-15728, 2007. </b> </p> <p class='abstract'> The photosynthetic unit (PSU) of purple photosynthetic bacteria consists of a network of bacteriochlorophyll (BChl) protein complexes that absorb solar energy for eventual conversion to ATP. Due to its remarkable simplicity, the PSU can serve as a prototype for studies of cellular organelles. In the purple bacterium <EM>Rhodobacter (Rb.) sphaeroides</EM> the PSU forms spherical invaginations of the inner membrane, approximately 70nm in diameter, composed mostly of light harvesting complexes, LH1 and LH2, as well as reaction centers (RCs). Atomic force microscopy (AFM) studies of the intracytoplasmic membrane have revealed the overall spatial organization of the PSU. In the present study these AFM data were used to construct three-dimensional models of an entire membrane vesicle at the atomic level, using the known structure of the LH2 complex and a structural model of the dimeric RC-LH1 complex. Two models depict vesicles consisting of 9 or 18 dimeric RC-LH1 complexes and 144 or 101 LH2 complexes, representing a total of 3879 or 4464 Bchls, respectively. The <EM>in silico</EM> reconstructions permit a detailed description of light absorption and electronic excitation migration, including computation of a 50 ps excitation lifetime and a 95 % quantum efficiency for one of the model membranes, and demonstration of excitation sharing within the closely packed RC-LH1 dimer arrays. </p> <p class='request'> <a href='http://www.ks.uiuc.edu/Publications/Papers/request.cgi?tbcode=SENE2007'>Full Text</a> </p> http://www.ks.uiuc.edu/Publications/Papers/paper.cgi?tbcode=SENE2007