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

Investigating the Properties of Fatty Acid-based Ionic Liquids: Advancement in AMOEBA Force Field

Developing the multipolar-polarizable AMOEBA force field for large molecules presents its own set of complexities. However, by segmenting the molecules into smaller fragments and ensuring that each fragment is transferable to other systems, the process of parameterizing large molecules such as fatty acids can be simplified without compromising accuracy. In this study, we present a fragment- based AMOEBA FF development for long-chain fatty acid ionic liquids (LCFA-ILs). AMOEBA enables us to incorporate polarization to measurably enhance the precision in modeling these large highly charged systems. This is of significant importance since the computational investigation of ILs needs accurate modeling. Additionally, to leverage the tunability of ILs, it is essential to test numerous anion and cation combinations to identify the most suitable formulation for each application. However, conducting such experiments can be resource-intensive and time-consuming, but accurate molecular modeling can expedite the exploration process. Here, the newly developed parameters were evaluated by comparing the decomposed intermolecular interaction energies for ion pairs with energies determined by quantum mechanics calculations as a reference. By employing this FF in molecular dynamics simulations, we predicted bulk and structural properties including density, enthalpy of vaporization, diffusion coefficient, and radial distribution function of diverse LCFA-ILs. Notably, the good agreement between the experimental data and those calculated using our parameters validates the accuracy of our methodology. Therefore, this new procedure provides an accurate approach to parameterizing large systems, paving the way for studying more complicated systems such as lipids, polymers, micelles and membrane proteins

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

Allosteric Modulation of the YAP/TAZ-TEAD Interaction by Palmitoylation and Small-Molecule Inhibitors

The Hippo signaling pathway is a highly conserved signaling network that plays a central role in regulating cellular growth, proliferation, and organ size. This pathway consists of a kinase cascade that integrates various upstream signals to control the activation or inactivation of YAP/TAZ proteins. Phosphorylated YAP/TAZ is sequestered in the cytoplasm; however, when the Hippo pathway is deactivated, it translocates into the nucleus, where it associates with TEAD transcription factors. This partnership is instrumental in regulating the transcription of progrowth and antiapoptotic genes. Thus, in many cancers, aberrantly hyperactivated YAP/TAZ promotes oncogenesis by contributing to cancer cell proliferation, metastasis, and therapy resistance. Because YAP and TAZ exert their oncogenic effects by binding with TEAD, it is critical to understand this key interaction to develop cancer therapeutics. Previous research has indicated that TEAD undergoes autopalmitoylation at a conserved cysteine, and small molecules that inhibit TEAD palmitoylation disrupt effective YAP/TAZ binding. However, how exactly palmitoylation contributes to YAP/TAZ-TEAD interactions and how the TEAD palmitoylation inhibitors disrupt this interaction remains unknown. Utilizing molecular dynamics simulations, our investigation not only provides detailed atomistic insight into the YAP/TAZ-TEAD dynamics but also unveils that the inhibitor studied influences the binding of YAP and TAZ to TEAD in distinct manners. This discovery has significant implications for the design and deployment of future molecular interventions targeting this interaction

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