Classical And Quantum Mechanical Simulations Of Condensed Systems And Biomolecules

This work describes the fundamental study of two enzymes of Fe(II)/-KG super family enzymes (TET2 and AlkB) by applying MD and QM/MM approaches, as well as the development of multipolar-polarizable force field (AMOEBA/GEM-DM) for condensed systems (ionic liquids and water). TET2 catalytic activity has been studied extensively to identify the potential source of its substrate preference in three iterative oxidation steps. Our MD results along with some experimental data show that the wild type TET2 active site is shaped to enable higher order oxidation. We showed that the scaffold stablished by Y1902 and T1372 is required for iterative oxidation. The mutation of these residues perturbs the alignment of the substrate in the active site, resulting in “5hmC-stalling” phenotype in some of the mutants. We provided more details on 5hmC to 5fC oxidation mechanism for wild type and one of the “5hmC-stallling” mutants (E mutant). We showed that 5hmC oxidizes to 5fC in the wild type via three steps. The first step is the hydrogen atom abstraction from hydroxyl group of 5hmC, while the second hydrogen is transferred from methylene group of 5hmC through the third transition state as a proton. Our results suggest that the oxidation in E mutant is kinetically unfavorable due to its high barrier energy. Many analyses have been performed to qualitatively describe our results and we believed our results can be used as a guide for other researchers. In addition, two MD approaches (explicit ligand sampling and WHAM) are used to study the oxygen molecule diffusion into the active site of AlkB. Our results showed that there are two possible channels for oxygen diffusion, however, diffusion through one of them is thermodynamically favorable. We also applied multipolar-polarizable force field to describe the oxygen diffusion along the preferred tunnel. We showed that the polarizable force field can describe the behavior of the highly polarizable systems accurately. We also developed a new multipolar-polarizable force field (AMOEBA/GEM-DM) to calculate the properties of imidazolium- and pyrrolidinium- based ionic liquids and water in a range of temperature. Our results agree well with the experimental data. The good agreement between our results and experimental data is because our new parameters provide an accurate description of non-bonded interactions. We fit all the non-bonded parameters against QM. We use the multipoles extracted from fitted electron densities (GEM) and we consider both inter- and intra-molecular polarization. We believe this method can accurately calculate the properties of condensed systems and can be helpful for designing new systems such as electrolytes

Exploring the Role of Interfacial Cation in F Ion Channel using MD Simulation: Application of Computational Chemistry

For many microbes, fluoride ion (F-) is toxic in high concentrations. To resist Ftoxicity, microbes have evolved a resistance mechanism, in which the Fluc channel exports Fions with high selectivity. Fluc has several unique features including a dual topology dimeric architecture. It has been shown that a Na+ ion is located at the interface of the dimer, however, the proposed Na+ is tetrahedrally coordinated while Na+ usually coordinates with 5 or 6 ligands. This study provides details about the role of a tetrahedrally–coordinated sodium ion in the structural stability and aid in identifying the contributing residues in high Fselectivity. We are modeling Fluc with various cations including Mg2+ and Mn4+ to provide a comprehensive comparison of Fluc structural stability and conformational changes. This research proposes an alternate interfacial ion for Fluc and could have larger implications for future study of this channel and other cation-coupled transporters for antimicrobial drug design

Modeling Molecular Interactions in Water: From Pairwise to Many-Body Potential Energy Functions.

Almost 50 years have passed from the first computer simulations of water, and a large number of molecular models have been proposed since then to elucidate the unique behavior of water across different phases. In this article, we review the recent progress in the development of analytical potential energy functions that aim at correctly representing many-body effects. Starting from the many-body expansion of the interaction energy, specific focus is on different classes of potential energy functions built upon a hierarchy of approximations and on their ability to accurately reproduce reference data obtained from state-of-the-art electronic structure calculations and experimental measurements. We show that most recent potential energy functions, which include explicit short-range representations of two-body and three-body effects along with a physically correct description of many-body effects at all distances, predict the properties of water from the gas to the condensed phase with unprecedented accuracy, thus opening the door to the long-sought "universal model" capable of describing the behavior of water under different conditions and in different environments

Computational investigation of O₂ diffusion through an intra-molecular tunnel in AlkB; influence of polarization on O₂ transport

This article discusses the use of computational simulations to investigate possible migration pathways inside AlkB for O₂ molecules

Insight into wild-type and T1372E TET2-mediated 5hmC oxidation using ab initio QM/MM calculations

This article studies the catalytic mechanism of oxidation of 5hmC to 5fC by WT and T1372E TET2 using an ab initio quantum mechanical/molecular mechanical (QM/MM) approach

Uncovering the Mechanism of the Proton-Coupled Fluoride Transport in the CLC^F Antiporter

Fluoride is a natural antibiotic abundantly present in the environment and, in micromolar concentrations, is able to inhibit enzymes necessary for bacteria to survive. However, as is the case with many antibiotics, bacteria have evolved resistance methods, including through the use of recently discovered membrane proteins. One such protein is the CLCF F–/H+ antiporter protein, a member of the CLC superfamily of anion-transport proteins. Though previous studies have examined this F– transporter, many questions are still left unanswered. To reveal details of the transport mechanism used by CLCF, we have employed molecular dynamics simulations and umbrella sampling calculations. Our results have led to several discoveries, including the mechanism of proton import and how it is able to aid in the fluoride export. Additionally, we have determined the role of the previously identified residues Glu118, Glu318, Met79, and Tyr396. This work is among the first studies of the CLCF F–/H+ antiporter and is the first computational investigation to model the full transport process, proposing a mechanism which couples the F– export with the H+ import

Development of AMOEBA Force Field for 1,3-Dimethylimidazolium Based Ionic Liquids

The development of AMOEBA (a multipolar polarizable force field) for imidazolium based ionic liquids is presented. Our parametrization method follows the AMOEBA procedure and introduces the use of QM intermolecular total interactions as well as QM energy decomposition analysis (EDA) to fit individual interaction energy components. The distributed multipoles for the cation and anions have been derived using both the Gaussian distributed multipole analysis (GDMA) and Gaussian electrostatic model-distributed multipole (GEM-DM) methods. The intermolecular interactions of a 1,3-dimethylimidazolium [dmim⁺] cation with various anions, including fluoride [F^–], chloride [Cl^–], nitrate [NO₃^–], and tetraflorouborate [BF₄^–], were studied using quantum chemistry calculations at the MP2/6-311G­(d,p) level of theory. Energy decomposition analysis was performed for each pair using the restricted variational space decomposition approach (RVS) at the HF/6-311G­(d,p) level. The new force field was validated by running a series of molecular dynamic (MD) simulations and by analyzing thermodynamic and structural properties of these systems. A number of thermodynamic properties obtained from MD simulations were compared with available experimental data. The ionic liquid structure reproduced using the AMOEBA force field is also compared with the data from neutron diffraction experiment and other MD simulations. Employing GEM-DM force fields resulted in a good agreement on liquid densities ρ, enthalpies of vaporization Δ<i>H</i>_vap, and diffusion coefficients <i>D</i>_± in comparison with conventional force fields

Biophysical and in silico characterization of NrtA: A protein-based host for aqueous nitrate and nitrite recognition

Nitrate and nitrite are key components of the global nitrogen cycle. As such, Nature has evolved proteins as biological supramolecular hosts for the recognition, translocation, and transformation of both nitrate and nitrite. To understand the supramolecular principles that govern these anion-protein interactions, here, we employ a hybrid biophysical and in silico approach to characterize the thermodynamic properties and protein dynamics of NrtA from the cyanobacterium Synechocystis sp. PCC 6803 for the recognition of nitrate and nitrite

Tinker-HP: a Massively Parallel Molecular Dynamics Package for Multiscale Simulations of Large Complex Systems with Advanced Point Dipole Polarizable Force Fields

International audienceWe present Tinker-HP, a massively MPI parallel package dedicated to classical molecular dynamics (MD) and to multiscale simulations, using advanced polarizable force fields (PFF) encompassing distributed multipoles electrostatics. Tinker-HP is an evolution of the popular Tinker package code that conserves its simplicity of use and its reference double precision implementation for CPUs. Grounded on interdisciplinary efforts with applied mathematics, Tinker-HP allows for long polarizable MD simulations on large systems up to millions of atoms.We detail in the paper the newly developed extension of massively parallel 3D spatial decomposition to point dipole polarizable models as well as their coupling to efficient Krylov iterative and non-iterative polarization solvers. The design of the code allows the use of various computer systems ranging from laboratory workstations to modern petascale supercomputers with thousands of cores. Tinker-HP proposes therefore the first high-performance scalable CPU computing environment for the development of next generation point dipole PFFs and for production simulations. Strategies linking Tinker-HP to Quantum Mechanics (QM) in the framework of multiscale polarizable self-consistent QM/MD simulations are also provided. The possibilities, performances and scalability of the software are demonstrated via benchmarks calculations using the polarizable AMOEBA force field on systems ranging from large water boxes of increasing size and ionic liquids to (very) large biosystems encompassing several proteins as well as the complete satellite tobacco mosaic virus and ribosome structures. For small systems, Tinker-HP appears to be competitive with the Tinker-OpenMM GPU implementation of Tinker. As the system size grows, Tinker-HP remains operational thanks to its access to distributed memory and takes advantage of its new algorithmic enabling for stable long timescale polarizable simulations. Overall, a several thousand-fold acceleration over a single-core computation is observed for the largest systems. The extension of the present CPU implementation of Tinker-HP to other computational platforms is discussed