Study of GroEL Conformational Mobility by Cryo-Electron Microscopy and Molecular Dynamics

In this study, the reliability of classical molecular dynamics (MD) method to thermodynamic properties of cryogenic hydrogen was investigated. The Lennard-Jones (LJ) potential, 2-Center Lennard-Jones (2CLJ) potential and modified Buckingham (exp-6) potential were applied for this investigation. MD calculations were conducted at a wide density-temperature range. The Equation of State (EOS) obtained by the MD results was calculated using Kataoka’s method, and they were compared with NIST (National Institute of Standards and Technology) data. As a result, it was confirmed that the thermal properties obtained by MD results can reproduce the NIST data at gas phase, while it cannot at liquid phase and around its critical point. These distinctions are considered to arise from the manybody effect or quantum effect of actual hydrogen liquid.

Molecular dynamics and first-principles studies of structural change in 1,3,5-triamino-2,4,6-trinitrobenzene (TATB) in crystalline state under high pressure: Comparison of hydrogen bond systems of TATB versus 1,3-diamino-2,4,6-trinitrobenzene (DATB)

Prediction of the morphology of the as-implanted damage in silicon using a novel combination of BCA and MD simulations

Hybrid structure fitting methods combine data from cryo-electron microscopy and X-ray crystallography with molecular dynamics simulations for the determination of all-atom structures of large biomolecular complexes. Evaluating the quality-of-fit obtained from hybrid fitting is computationally demanding, particularly in the context of a multiplicity of structural conformations that must be evaluated. Existing tools for quality-of-fit analysis and visualization have previously targeted small structures and are too slow to be used interactively for large biomolecular complexes of particular interest today such as viruses or for long molecular dynamics trajectories as they arise in protein folding. We present new data-parallel and GPU-accelerated algorithms for rapid interactive computation of quality-of-fit metrics linking all-atom structures and molecular dynamics trajectories to experimentally-determined density maps obtained from cryo-electron microscopy or X-ray crystallography. We evaluate the performance and accuracy of the new quality-of-fit analysis algorithms vis-à-vis existing tools, examine algorithm performance on GPU-accelerated desktop workstations and supercomputers, and describe new visualization techniques for results of hybrid structure fitting methods.

The solution conformations of methyl β-D-galactopyranosyl-(1 → 2)-xylopyranoside (1) and methyl α-L-fucopyranosyl-(1 → 2)-β-D-galactopyranosyl-(1 → 2)-xylopyranoside (2) have been analysed by NMR spectroscopy and molecular mechanics and dynamics calculations. The comparison between NMR experimental results (NOES based on NOESY, ROESY, T-ROESY and steady-state experiments) and expected data [from ensemble average distributions of conformers and molecular dynamics (MD) simulations] indicates that both compounds present a moderate flexibility around their glycosidic linkages. A van der Waals interaction between the remote fucopyranosyl and xylopyranosyl moieties of 2 can be deduced from the theoretical and experimental data.

Multiscale Computational Modeling of Tubulin-Tubulin Lateral Interaction

Silicon carbide (SiC) is a promising structural and cladding material for accident tolerant fuel cladding of nuclear reactor due to its excellent properties. However, when exposed to severe environments (e.g., during neutron irradiation), lattice defects are created in amounts significantly greater than normal concentrations. Then, a series of radiation damage behaviors (e.g., radiation swelling) appear. Accurate understanding of radiation damage of nuclear materials is the key to the design of new fuel cladding materials. Multi-scale computational simulations are often required to understand the physical mechanism of radiation damage. In this work, the effect of neutron irradiation on the volume swelling of cubic-SiC film with 0.3 mm was studied by using the combination of molecular dynamics (MD) and rate theory (RT). It was found that for C-vacancy (CV), C-interstitial (CI), Si-vacancy (SiV), Si-interstitial (SiI), and Si-antisite (SiC), the volume of supercell increases linearly with the increase of concentration of these defects, while the volume of supercell decreases linearly with the increase of defect concentration for C-antisite (CSi). Furthermore, according to the neutron spectrum of a certain reactor, one RT model was constructed to simulate the evolution of point defect under neutron irradiation. Then, the relationship between the volume swelling and the dose of neutrons can be obtained through the results of MD and RT. It was found that swelling typically increases logarithmically with radiation dose and saturates at relatively low doses, and that the critical dose for abrupt transition of volume is consistent with the available experimental data, which indicates that the rate theory model can effectively describe the radiation damage evolution process of SiC. This work not only presents a systematic study on the relationship between various point defect and excess volume, but also gives a good example of multi-scale modelling through coupling the results of binary collision, MD and RT methods, etc., regardless of the multi-scale modelling only focus on the evolution of primary point defects.

This Ph.D. thesis describes three research projects in theoretical and computational biophysics aimed at studying the dynamics of water and lipid molecules in two distinct biomolecular systems. In the first project the energetics and dynamics of water transport through the aquaglyceroporin (GlpF) channel protein is studied by a combination of all-atom molecular dynamics (MD) simulations (both equilibrium and non-equilibrium MD) and stochastic modeling. The MD results are used to determine the potential of mean force and the diffusion coefficient of water molecules crossing the channel. Then, the latter quantities are used to estimate the intrinsic water flux through GlpF, and the corresponding channel permeability. In the second project, by employing a 0.1 micro second long, all-atom MD simulation, the self and correlated dynamics of lipid atoms and molecules in a fully hydrated DMPC lipid bilayer is investigated. The MD simulation results are used to develop a memory function based approach for accurately calculating the lateral self-diffusion coefficient of lipids. In some cases, the proposed memory function method provides a better approach than the currently used ones for determining the lateral diffusion coefficient of lipids in lipid bilayers from the dynamic structure factor measured in inelastic neutron scattering experiments. The purpose of the third project is to investigate the dynamics of water molecules in a hydrated lipid membrane. Using the same MD simulation as in the second project, the anomalous properties of buried and hydration waters (located at the proximity of the fluctuating surface of the lipid membrane) are revealed and contrasted to the properties of bulk water.

A set of molecular dynamics computer simulation studies applied in protein design is reviewed. The picture begins to emerge that with present day force fields and molecular dynamics simulation techniques the essentials of proteins’ structural and dynamical features around their native states may be obtained. The perspective of computer simulation as a tool in molecular engineering is explored. We discuss modelling of collective motion in proteins’ secondary structural elements, thermal stability of protein structures, differential stability in protein folds and surface plasticity properties of proteins. Properties of the following proteins are touched: the carboxy terminal fragment of the L7/L12 ribosomal protein from Escherichia coli, the potato carboxypeptidase A protein inhibitor, bacteriophage T4 glutaredoxin and the retinol binding protein. Appended are discussions of the chemical mechanism of hydride transfer in horse liver alcohol dehydrogenase, the fundamentals of interactive dynamical computer graphics analysis and a survey of the theoretical framework of molecular dynamics simulations.

SummaryChaperonins play an important role in folding newly synthesized or translocated proteins in all organisms. The bacterial chaperonin GroEL has served as a model system for the understanding of these proteins. In comparison, its human homolog, known as mitochondrial heat shock protein family member D1 (HSPD1) is poorly understood. Here, we present the structure of HSPD1 in the apo state determined by cryo-electron microscopy (cryo-EM). Unlike GroEL, HSPD1 forms mostly single ring assemblies in the absence of co-chaperonin (HSPE1). Comparison with GroEL shows a rotation and increased flexibility of the apical domain. Together with published structures of the HSPD1/HSPE1 co-chaperonin complex, this work gives insight into the structural changes that occur during the catalytic cycle. This new understanding of HSPD1 structure and its rearrangements upon complex formation may provide new insights for the development of HSPD1-targeting treatments against a diverse range of diseases including glioblastoma.

The extended fine structure on the X-ray absorption cross section (EXAFS) depends sensitively upon the details of the nearest-neighbour peak in the atom-atom pair correlation function. It follows that EXAFS data can be helpful in determining the short-range portion of atom-atom pair interaction potentials such as are the starting point for molecular dynamics (MD) calculations. The cation-anion pair correlation functions g(r) obtained from MD calculations on superionic AgI and CuI are compared with EXAFS data. The nearest-neighbour peak in the MD g(r) begins at too short a cation-anion separation and is too broad to be consistent with the data. The causes and ramifications of this are discussed.

A synergic approach combining molecular dynamics (MD) simulations and X-ray absorption spectroscopy (XAS) has been used to investigate diluted (0.1 M) aqueous solutions of two lanthanide ions (Ln3+), namely, La3+ and Dy3+, with triflate, nitrate, and bis(trifluoromethylsulfonyl)imide (Tf2N-) as counterions. The different complexing ability of the three anions has been highlighted by the analysis of the MD simulations: Tf2N- does not form inner-sphere complexes, while a small amount of triflate coordinates both the La3+ and Dy3+ cations in their first solvation shell. On the other hand, the nitrate ion is almost absent in the La3+ first coordination sphere, while forming contact ion pairs with Dy3+. Both lanthanide ions are found to preferentially interact with the water molecules, and the total number of oxygen atoms coordinating the Ln3+ cations in their first solvation sphere is the same in all of the solutions, regardless of whether they belong to water molecules or to the counterion. The presence of counterions in the cation first or second shell changes neither the first shell distance nor the symmetry of the hydration complex formed in solution. The MD results have been confirmed by comparison with the Ln K-edge XAS experimental data, and the quantitative analysis of the extended X-ray absorption fine structure (EXAFS) spectra of the three salt solutions has provided a definite proof of the accuracy of the force field employed in the simulations and of the MD structural result. The anion-water and water-water hydrogen bond lifetimes have been analyzed highlighting the slow down effect of the triflate, nitrate, and Tf2N- anions on the hydrogen bond dynamics in the Ln3+ first solvation shell, with the effect being stronger in the Dy3+ solutions, due to the higher charge density of the Dy3+ ion as compared to La3+.

Novel technique for radioactive tracer diffusion measurements applied to Cu + diffusion in CuI

In this study, the thermal denaturation mechanism and secondary structures of two types of human insulin nanoparticles produced by a process of solution-enhanced dispersion by supercritical fluids using dimethyl sulfoxide (DMSO) and ethanol (EtOH) solutions of insulin are investigated using spectroscopic approaches and molecular dynamics calculations. First, the temperature-dependent IR spectra of spherical and rod-shaped insulin nanoparticles prepared from DMSO and EtOH solution, respectively, are analyzed using principal component analysis (PCA) and 2D correlation spectroscopy to obtain a deeper understanding of the molecular structures and thermal behavior of the two insulin particle shapes. All-atom molecular dynamics (AAMD) calculations are performed to investigate the influence of the solvent molecules on the production of the insulin nanoparticles and to elucidate the geometric differences between the two types of nanoparticles. The results of the PCA, the 2D correlation spectroscopic analysis, and the AAMD calculations clearly reveal that the thermal denaturation mechanisms and the degrees of hydrogen bonding in the spherical and rod-shaped insulin nanoparticles are different. The polarity of the solvent might not alter the structure or function of the insulin produced, but the solvent polarity does influence the synthesis of different shapes of insulin nanoparticles.

Entecavir, triphosphorylated in liver cells, is an antiviral reagent against Hepatitis B virus (HBV). The reagent inhibits reverse transcription of RNA inside the virus capsid. In the present study, free energy profile of an Entecavir triphosphate (ETVTP) molecule has been calculated when it passes through pores of the capsid along two- and three-fold rotational symmetry axes in order to investigate permeation pathway of the reagent to the inside of the capsid. The calculations have been done based on thermodynamic integration (TI) method combined with all-atomistic molecular dynamic (MD) calculations. A free energy minimum of −19 kJ/mol was found at the entrance of the pore from the outside along the three-fold symmetry axis. This stabilization is from the interaction of negatively charged ETVTP with positively charged capsid methionine residues. This excess free energy concentrates of the reagent at the entrance of the pore by a factor of about 2000. A free energy barrier of approximately 13 kJ/mol was also found near the exit of the pore to the inside of the capsid due to narrow space of the pore surrounded by hydrophobic wall made by proline residues and negatively charged wall by aspartic acid residues. There, ETVTP is partially dehydrated in order to pass through the narrow space, which causes the great free energy loss. Further, the negatively charged residues produce repulsive forces on the ETVTP molecule. In contrast, in the case of the pore along the two-fold symmetry axis, the calculated free energy profile showed shallower free energy minimum, −4 kJ/mol at the entrance in spite of the similarly high barrier, 7 kJ/mol, near the exit of the pore.