Bora, Ram Prasad, Department of Chemistry, University of Miami 

Computational Insights into the Enzyme-substrate (Aβ40 and Aβ42) Interactions and the Catalytic Mechanism of Insulin Degrading Enzyme (IDE)    

Abstract: Insulin degrading enzyme (IDE) is a Zn-containing metallopeptidase involved in the degradation of the monomeric forms of amyloidogenic substrates such as insulin-B chain and Alzheimer’s amyloid beta peptides (Aβ40 and Aβ42). The up-regulating of this enzyme and designing of drug molecules that can mimic its activity represent promising therapeutic avenues for the treatment of Alzheimer’s disease.We have performed molecular dynamics (MD) simulations to study the conformational occupancy and the interactions of the full-length substrates, Aβ40 and Aβ42, in the catalytic chamber of IDE in its active form. Our simulations showed that the substrates undergo conformational changes inside the catalytic chamber and the cleavage sites lie in the vicinity of the active site of the enzyme. We have also investigated the mechanisms for the hydrolysis of Phe-Phe, His-Gln and Lys-Gly peptide bonds of Aβ40 by IDE at the B3LYP level. The computed barrier of 14.3 kcal/mol for the hydrolysis of Lys-Gly bond was found to be 4.1 and 8.0 kcal/mol lower than for Phe-Phe and His-Gln peptide bonds respectively.

Balabin, Ilya, Duke University

Coarse-grained modeling of signal transduction in GPCRs

Abstract: G protein-coupled receptors (GPCRs) are seven transmembrane-helix proteins that perform highly specific ligand binding and communicate a broad variety of signals across the cell membrane. Signal transduction in GPCRs is mediated by relatively subtle structural changes that are difficult to identify in the background of thermal fluctuations. We describe a new model of allosteric communications in GPCRs that addresses the fundamental riddle of signaling: the structural origin of the receptor agonism (specific signaling response). The model successfully identified the allosteric sites and the structural changes that mediate signal transduction in two GPCRs, human beta2-adremoreceptor and bovine rhodopsin. Implications are discussed for understanding the receptor agonism, particularly the recently observed "biased agonism" (selected activation of specific signaling pathways), and for
developing rational structure-based drug design strategies.

Carlen, Ben, UT Knoxville

X-ray absorption spectra within the core-hole approximation: Animplementation in NWChem 

Abstract: Density functional theory is used to calculate the core excitation spectraof Ti containing catalytic building blocks. Specifically, the core-holeapproximation is used. In this scenario, the excitation energies of coreelectrons are calculated using the approximation that the core energylevel be constrained to be unoccupied throughout the relaxation process ofthe other orbitals. This allows a more accurate determination of theresulting x-ray spectra. The method described has been integrated into NWChem.

Chen, Bin,  Louisiana State University 

Invited Talk:
Towards understanding the nucleation mechanism for multi-component systems: An atomistic approach 

Abstract: Despite decades of intense research efforts, the molecular details of atmospheric nucleation processes have been elusive and highly debated. Although laboratory experiments and field studies have provided important insights in the chemical species that are actively involved in these nucleation processes, there is very little information on the atomic-level structure of critical nuclei.The problem originates from the activated nature of these processes and the inherent difficulty in the direct probing of the critical nuclei as they are transient and their occurrence probabilities are extremely low. This presentation will focus on the recent development of the aggregation-volume-bias Monte Carlo (AVBMC) based simulation method and the application of this atomistic approach to the molecular-level characterization of various multi-component vapor--liquid nucleation processes. Topics will be selected from: (i) ternary nucleation of water, n-alkane, and alcohols; (ii) ion enhanced nucleation of water; and (iii) extension of the AVBMC technique to the crystal nucleation in supercooled clusters. 

Curtarolo, Stefano, Department of Mechanical Engineering and Materials Science,  Duke University

Invited Talk:
Disorder-order transitions in Fe nano-catalysts

Abstract: Fe and Fe:Mo nanoclusters are becoming the standard catalysts for growing single-walled carbon nanotubes (SWCNTs) via chemical vapor decomposition (CVD). Contrary to the Gibbs-Thomson formalism, experimental results show that reducing the size of the catalyst beyond a certain limit requires increasing the (minimum) growth temperature. This apparent paradox is addressed in terms of solubility of C in Fe nanoclusters. By using first principles calculations, an innovative thermodynamic model is constructed to determine the behavior of the phases competing for stability. As a function of particle size, there are three scenarios: steady state-, limited-, or no-growth of SWCNTs, corresponding to unaffected, reduced, and zero solubility of C in the clusters. The results are extended to Fe-Mo binary catalysts. The 15+ year long-standing question about the effects of Mo concentration on the growth capability is finally answered. Research sponsored by ACS and Honda. 

Phys. Rev. Lett. *100*, 195502 (2008), Phys. Rev. B, *77*, 115450 (2008),  Phys. Rev. B *75*, 205426 (2007). 

Czako, Gabor,  Emory University 

Accurate ab initio potential energy surface, dynamics, and thermochemistry of the F + CH4→ HF + CH3 reaction 

Abstract: There have been many experimental and theoretical studies of the gas-phase reactions of a halogen atom and a hydride molecule, e.g. H2, H2O, NH3, CH4 and their isotopologues. Among the atom+diatom systems the F + H2 → HF + H reaction has received a lot of attention. Since an atom+diatom system has "only" three internal degrees of freedom, the dynamics of the above-mentioned reaction have been studied by sophisticated quantum methods. In the case of an atom+polyatom reaction quasiclassical trajectory (QCT) calculations are frequently used in order to describe the nuclear dynamics. The QCT method propagates the nuclei classically while the required forces, i.e. potential gradients, are computed quantum mechanically by solving the related electronic Schrödinger equation. An accurate full-dimensional global potential energy surface (PES) for the F + CH4→ HF + CH3 reaction has been developed based on 19 384 UCCSD(T)/aug-cc-pVTZ quality ab initio energy points obtained by an efficient composite method employing explicit UCCSD(T)/aug-cc-pVDZ and UMP2/aug-cc-pVXZ [X = D, T] computations. The PES contains a first-order saddle point, (CH4--F)SP, separating reactants from products, and also minima describing the van der Waals complexes, (CH4---F)vdW and (CH3---HF)vdW, in the entrance and exit channels, respectively. The structures of these stationary points, as well as those of the reactants and products have been computed and the corresponding energies have been determined using basis set extrapolation techniques considering (a) electron correlation beyond the CCSD(T) level, (b) effects of the scalar relativity and the spin-orbit couplings, (c) diagonal Born-Oppenheimer corrections (DBOC), and (d) zero-point vibrational energies and thermal correction to the enthalpy. Variational vibrational calculations have been carried out for (CH3---HF)vdW in full (12) dimensions. QCT calculations of the reaction using the new PES are reported. The computed HF vibrational and rotational distributions are in excellent agreement with experiment.

Dominy, Brian, Clemson University

Towards a biophysical characterization of enzyme evolution

Abstract:  Enzymes evolve to optimize their catalytic efficiency in the context of a biochemical reaction network in part by stabilizing the transition state of a specific reaction. However, the physical chemical basis of enzyme evolution is not very well understood and the factors responsible for the optimization of catalytic efficiency during evolution have not been well quantified. In the context of transition state theory, free energy calculations within the classical charmm potential are applied to substrate and transition state analog complexes and used to estimate the impact of mutations on the activity of the HIV protease enzyme. These purely classical calculations are statistically shown to capture this activity information through comparison with recently published experimental results. A more detailed examination of the calculated binding energies suggests ground-state destabilization as a viable physical mechanism underlying the evolutionary optimization of this enzyme. An application of the Michealis-Menten rate laws in the context of the biological environment associated with the activity of HIV protease also supports the mechanism of ground-state destabilization. This study demonstrates that large-scale applications of free energy methods applied to classical molecular models can yield results that are predictive of changes in enzyme activity through mutation, and can also provide insight into the molecular and physical origins of enzyme evolution.

Gao, Yi Qin, Texas A&M University 

Invited Talk:
The hydrophobic and hydrogen bonding interactions in polypeptides

Abstract: An efficient sampling method was used to calculate the free energy landscape for the folding of polypeptides and small proteins. Special attention was paid to analyze the relations between the folding rate and the hydrophobicity of the side chains and between the strength of the backbone hydrogen bonds and the hydrophobicity. It was shown that the relative hydrogen bond strength correlates well with the hydrophobicity of its local environment. Urea denaturation simulations showed that the kinetics of hydrogen bond breaking (e.g., the order by which individual hydrogen bonds are broken) also correlates with the local environment of the hydrogen bonds. Further, these denaturation studies showed that the breaking of protein hydrogen bonds is more likely initiated by the attack of the amide groups by water molecules, although the denatured structure is stabilized by hydrogen bonds with both water and urea. These results suggest that urea denatures protein through bothdirect and indirect effects. The physical chemistry reason behind the effects of urea and other cosolvents (denaturants and osmolytes) will also be discussed.

Goldsmith, Michael-Rock, US-Environmental Protection Agency

Prenatal Plasma Proteins, Playstation 3 and Predictive models for Public Health: a-fetoprotein Alliterated

Abstract: "Who has seen the abominable α-fetoprotein (AFP)?" Although perhaps one of the most studied proteins (> 10,000 citations), surprisingly very few structural studies are available for human AFP. As the primary protein constituent of plasma in early gestation (throughout post-natal year 1), we ask what makes AFP, a member of the albumin family, so unique?In this study we develop homology models of AFP based on albumin scaffolds and compare and contrast differences between both structures on equal footing. We discuss several important differences that provide AFP privileged access to a critical developmental window, organogenesis.We also discuss the structural, electrostatic, and biophysics of the modeled structure in the context of biology, and explore the implications of variations between its cousin, albumin, on a site-by-site basis: a "Trojan-horse" in a unique and complex environment.We further refine these models with libraries of ligands known to bind to AFP and develop a virtual screening tool to discern preferential binding of ligands to AFP versus albumin.We use the tool to screen a library of FDA-approved drugs, environmental chemicals, nutritional chemicals and lifestyle chemicals using an ultra-high-throughput molecular docking code optimized for the parallel GPU architecture of modern computer gaming devices, and discuss AFP-enabled selectivity as a result of these experiments.These in silico studies provide an added incentive to invest efforts in both structural studies on AFP, and development of both structure and ligand-based approaches to compare and contrast chemical space determinants of selectivity for adult (albumin) and early life-stage (AFP) plasma binding that may assist in elucidating life-stage specific body-burden and dose-enablement.  

Invited Talk:
Catalysis and conformational dynamics of well structured wild-type and molten globular mutant chorismate mutases

Abstract: We simulated the reactions catalyzed by the well folded wild-type and the molten globular mutant chorismate mutases, focusing on the origin of the catalytic power of the molten globular enzyme and the change of enzyme conformational dynamics along the reaction processes. With the ab initio QM/MM minimum free-energy path method, we were able to determine the height of reaction barriers in good agreement with experimental measurement. The interactions between the enzyme and substrate were analyzed in detail to reveal the interactions responsible for the catalysis. Examining the conformational dynamics of the enzyme reveals the different dynamic transitions between the reactant and transition states, for the wild-type and mutant enzymes, respectively.
Our results provided new insights into the important topic for the correlation between conformational dynamics and enzyme catalysis.

Johnson, Erin, Duke University 

Implications of Delocalization Error for Thermochemistry and Bonding 

Abstract: We discuss the performance of approximate density functionals for main-group thermochemistry from the perspective of the delocalization error. This error causes approximate functionals to give too low energy for delocalized electron densities, as in highly conjugated systems. Conversely, our findings imply that there is a region of highly localized electron density in bicyclic rings and sterically crowded systems that is under-stabilized by functionals with inherent delocalization error. Examination of properties of the density and its reduced gradient reveals that such localized regions are characteristic of non-covalent interactions, including steric repulsion, pi-stacking, and hydrogen-bonding.

Kosov, Daniel, University of Maryland and Universite Libre de Bruxelles (Belgium)

Invited Talk:
Attosecond Chemistry 

Abstract: In atoms and molecules electrons move, interact and and exchange places on the attosecond (10^{-18} s) time scale. All standard pictures (molecular orbitals, atomic orbitals, or band structure) are valid only when electron dynamics is slow enough so that the electrons have enough time to adjust to produce a mean field.Attosecond spectroscopy has been recently used to capture experimentally multi-electron dynamicsin real time providing for the first time direct time-domain insight into electron-electron correlations.In my talk I will first review recent attosecond experiments relevant to multi-electron dynamics in molecules, then I will discuss theoretical approaches to describe collective ultra-fast responses of correlated many-particle systems.

Papoian, Garegin,  UNC Chapel Hill 

Invited Talk:
Atomistic and Coarse-Grained Modeling of DNA and Chromatin 

Abstract: DNA undergoes very large compactification in cells of higher organisms. We are developing coarse-grained computational models that would allow simulating the way thousands of DNA base pairs and tens of thousands of protein residues interact to condense into a higher order structure, called chromatin. Towards this goal, we have recently derived a coarse grained force field for DNA, using renormalization group inspired technique, which has been rigorously validated against accurate all-atom simulations. We have also applied this approach to coarse-grain simple electrolyte solutions, which, in turn, allows us to include explicit ions in coarse-grained polyelectrolyte models. In a related study, our atomistic computer simulations of a nucleosome, the basic DNA-protein complex unit, allowed us to rationalize condensation of mobile counterion around these biomolecules. These calculations are used in an ongoing work to coarse-grain electrostatic interactions in the nucleosomal core particle.

Park, Kyungwha, Virgina Tech 

Electron transport through the single-molecule magnet Mn12 

Abstract:Single-molecule nanomagnets drew great attention due to their intriguing quantum properties despite their large magnetic moments.Recently, there have been a large amount of efforts to build and characterize monolayers of single-molecule nanomagnets and single-molecule nanomagnets bridged between electrodes.There were also theoretical efforts to study such systems based on many-body model Hamiltonians.However, there is still lack of understanding effects of local environmental factors on electron transport through single-molecule magnets.We investigate the electron transport through the single molecule magnet Mn12 using the non-equilibrium Green's function method in conjunction with density-functional theory.Considering two representative molecular geometries relative to electrodes and different interfaces/contacts, we discuss the coupling constant between the Mn12 and the electrodes and the charge distribution of conduction electrons over the Mn12, as well as current-voltage characteristics.

Rassolov, Vitaly, University of South Carolina 

Invited Talk:
Semi-classical electron correlation operator 

Abstract: We revisit a concept of a correlation operator, introduced 10 years ago as a possible method to model electron correlation effects with single determinant wavefunctions.First, we reviewvarious original hand-waving arguments that point to a general form of such an operator.Next, we show that a semi-classical approach yields the specific form of a correlation operator.Finally, we apply it to few model system and discuss merits and challenges of using this correlation operator to study chemical problems.

Valeev, Edward, Virginia Tech

Invited Talk:
Recent advances in explicitly-correlated electronic structure methods

Abstract: Many problems in molecular sciences (bond energetics, spectroscopy, weak interactions, etc.) require highly-accurate and systematically-improvable description of electronic structure. The traditional many-body methods, such as the celebrated coupled-cluster (CC) method, can be used to approach the exact solution, but are severely limited by the slow convergence of the error with respect to the size of the basis set. This so-called basis set problem of the many-body methods is rooted in the inappropriate form of the many-electron expansions used in the traditional methods. Here I will briefly review the history of explicitly-correlated many-body methods, which can be considered the first-principles solution to the basis set problem, and discuss the recent development of practical R12 methods pursued in several groups around the world. In particular, I will highlight our group's work in the area of perturbative R12 methods, which are especially simple without any loss of robustness. We typically observe that an R12 method need only a modest triple-zeta basis set to match the precision of its more expensive quintuple-zeta standard counterpart. In closing I will discuss a universal R12 approach that can be used to improve any traditional and non-traditional many-body methods.

Wang, Yongmei, University of Memphis

Mutliscale Modeling of DNA condensation by polycations 

Abstract:The condensation of DNA helices into compact bundles by multivalent cations has long been studied because of its importance to several experimental and biological processes. Recently, the prospect of condensing DNA with long polycations has been investigated for the potential use of DNA-polycation complexes in gene therapy treatments. Despite the great interest in using polycations as gene therapy vectors, currently available polycation-based gene therapy treatments are insufficient and suffer from a lack of knowledge of the basic physics that govern the formation of DNA-polycation complexes and their structures. Many aspects of DNA condensation by polycations are not well understood. We have thus performed fully atomistic simulation of DNA condensation by polyethyleimine (PEI) and poly-L-lysine (PLL). The simulation revealed a great deal of useful structural information about DNA-polycation complex formation. This talk will present our computational investigationon DNA condensation by polycations and how these computational investigation have improved the understanding of DNA condensation by polycations.

Yingling, Yaroslava, North Carolina State University 

Understanding self-assembly of nucleic acids into advanced materials 

Abstract: Nucleic Acid molecules can be engineered into novel nanostructutures using the straightforward molecular recognition properties of base pairing. However, the structures are not determined by base pairing alone and unpaired residues play a critical role in nanodesign and superassembly. Yet there is a limited understanding of the rules of formation of RNA and DNA materials. For successful design we need to understand and control the intermolecular associations, natural tendency, favorability and various physical components. We use molecular dynamics to understand the processes driving the self-assembly processes of natural and synthetic nucleic acids. We discovered that in nanoparticles and most organisms the loop-loop assembly process depends on the presence of electronegative and hydration channel. The properties of these channels and the sequence determines the stability, the hydrogen bonding interactions and the angle of the distinct kink between stems. We also show that in layer by layer assembly of nucleic acids films the length of a stem is crucial for the accumulation of the film.

Zhao, Xiongce,  Oak Ridge National Laboratory 

Invited Talk:
Simulation study of interaction between DNA and C60 

Abstract: Molecular dynamics simulations are performed to study the binding of C60 or its derivatives with DNA segments in aqueous solution. Despite the hydrophobic nature of C60, our results show that fullerenes strongly bind to nucleotides and form stable C60-DNA hybrids, with binding energies five times larger than that for two fullerenes in aqueous solution. C60 binds to double-strand DNA, either at the hydrophobic ends or at the minor groove of the nucleotide. C60 binds to single-strand DNA and deforms the nucleotides significantly. When the DNA molecule is damaged, fullerenes can stably occupy the damaged site. Simulations indicate that C60 derivatives also form stable hybrids with DNA segments, with binding energies similar to those of pristine C60 and DNA. But the interaction mechanism of C60 derivatives with DNA segments strongly dependent on the type and size of the functional groups. For C60 derivatives with a short functional group, the binding is still dominated by the hydrophobic force. In contrast, C60 derivatives with a long functional group can associates with DNA by entanglement of its hydrophilic chain to the backbone of the DNA through hydrogen bonds. For C60 derivatives with two short acid groups, two different types of interaction were observed, one dominated by hydrophobic interaction and the other one dominated by hydrogen bonds.

ZHU, RONGSHUN, Emory University 

CH3NO2 Decomposition/Isomerization Mechanism and Product Branching Ratio: An Ab Initio Chemical Kinetic Study 

Abstract: Nitromethane (NM) is an important model energetic material that could be used as an explosive and a propellant [1]. Its decomposition mechanism and kinetics are relevant to the energetic material as well as atmospheric pollution chemistry (e.g., CH₃ + NO₂). Experimentally, Wodtke, Hintsa, and Lee [2] reported the first experimental evidence for the direct production of CH₃O + NO from the infrared multi-photon dissociation (IRMPD) of NM under collision free conditions. Theoretically, the decomposition of NM has been studied by several investigators [3, 7-11].All of the previous calculations have not been able to account for the experimental finding that the rearrangement transition state lies below the dissociation limit CH₃ + NO₂ by 5.0±1.5 kcal/mol and that no clear picture for the decomposition mechanism has been provided to date.In this work, we mainly focus on our search for low-lying energy pathways with an attempt to address the above finding on the formation of CH₃O + NO with the NO/NO₂ product ratio of 0.6±0.2 or k_NO/k_total around (37.5±6) % [2] under collision free conditions by IRMPD. The low-lying energy pathways have been investigated using different molecular orbital methods. Our results show that the NM can isomerize to cis-CH₃ONO via a very loose transition state lying 59.2 (or 58.1) kcal/mol above CH₃NO₂ and 0.6 (or 2.7) kcal/mol below the CH₃ + NO₂ asymptote at the UCCSD(T)/CBS (or CASPT3(8,8)/6-311+G(3df,2p)//CAS(8,8)/6-311+G*) level. However, at the UCCSD(T)/CBS level, CH₃NO₂ isomerizes to trans-CH₃ONO via a tight transition state with a 9.4 kcal/mol barrier above CH₃ + NO₂. The loose transition state was also confirmed at the CAS(8,8)/6-311+G*,UMP2/6-311+G(3df,2p) and UCCSD/6-311+G* levels. Based on the UCCSD(T)/CBS energies, the predicted branching ratio for k_NO/(k_NO + k_NO2) lies between 38% and 44% in the energy range of 50.0 ~ 60.0 kcal/mol, which is in reasonable agreement with the experimental value, (37.3±0.6)%. Our results clarify for the first time the controversial decomposition/isomerization mechanism for CH₃O + NO formation in theIRMPD reaction.

# Corresponding author; email address: chemmcl@emory.edu; NSC DistinguishedVisiting Professor at NationalChiaoTungUniversity, Hsinchu, Taiwan.

*This work is sponsored in part by the Office of Naval Research under contract no. N00014 – 02-1-0133 

References

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Zou, Shengli,  Department of Chemistry, University of Central Florida 

Invited Talk:
Raman scattering enhancement and fluorescence quenching around a metal nanoparticle 

Abstract: Using electrodynamics and molecular dynamics method, we investigate the surface enhanced Raman scattering near metal nanoparticles and film surfaces. Enhanced local electric field near and far away from a film surface was investigated using the discrete dipole approximation method. The enhanced Raman scattering near a particle surface was examined with a driven force molecular dynamics method. The enhancement and quenching of the fluorescence signal of a molecule adjacent to a metal nanoparticle are explored with the coupled dipole approximation method.