Molecular Dynamics and Quantum Mechanics of RNA: Conformational and Chemical Change We Can Believe In

Structure and dynamics are both critical to RNA’s vital functions in biology. Numerous techniques can elucidate the structural dynamics of RNA, but computational approaches based on experimental data arguably hold the promise of providing the most detail. In this Account, we highlight areas wherein molecular dynamics (MD) and quantum mechanical (QM) techniques are applied to RNA, particularly in relation to complementary experimental studies

A comparative study between the cubic spline and b-spline interpolation methods in free energy calculations

Numerical methods are essential in computational science, as analytic calculations for large datasets are impractical. Using numerical methods, one can approximate the problem to solve it with basic arithmetic operations. Interpolation is a commonly-used method, inter alia, constructing the value of new data points within an interval of known data points. Furthermore, polynomial interpolation with a sufficiently high degree can make the data set differentiable. One consequence of using high-degree polynomials is the oscillatory behaviour towards the endpoints, also known as Runge's Phenomenon. Spline interpolation overcomes this obstacle by connecting the data points in a piecewise fashion. However, its complex formulation requires nested iterations in higher dimensions, which is time-consuming. In addition, the calculations have to be repeated for computing each partial derivative at the data point, leading to further slowdown. The B-spline interpolation is an alternative representation of the cubic spline method, where a spline interpolation at a point could be expressed as the linear combination of piecewise basis functions. It was proposed that implementing this new formulation can accelerate many scientific computing operations involving interpolation. Nevertheless, there is a lack of detailed comparison to back up this hypothesis, especially when it comes to computing the partial derivatives. Among many scientific research fields, free energy calculations particularly stand out for their use of interpolation methods. Numerical interpolation was implemented in free energy methods for many purposes, from calculating intermediate energy states to deriving forces from free energy surfaces. The results of these calculations can provide insight into reaction mechanisms and their thermodynamic properties. The free energy methods include biased flat histogram methods, which are especially promising due to their ability to accurately construct free energy profiles at the rarely-visited regions of reaction spaces. Free Energies from Adaptive Reaction Coordinates (FEARCF) that was developed by Professor Kevin J. Naidoo has many advantages over the other flat histogram methods. iii Because of its treatment of the atoms in reactions, FEARCF makes it easier to apply interpolation methods. It implements cubic spline interpolation to derive biasing forces from the free energy surface, driving the reaction towards regions with higher energy. A major drawback of the method is the slowdown experienced in higher dimensions due to the complicated nature of the cubic spline routine. If the routine is replaced by a more straightforward B-spline interpolation, sampling and generating free energy surfaces can be accelerated. The dissertation aims to perform a comparative study between the cubic spline interpolation and B-spline interpolation methods. At first, data sets of analytic functions were used instead of numerical data to compare the accuracy and compute the percentage errors of both methods by taking the functions themselves as reference. These functions were used to evaluate the performances of the two methods at the endpoints, inflections points and regions with a steep gradient. Both interpolation methods generated identically approximated values with a percentage error below the threshold of 1%, although they both performed poorly at the endpoints and the points of inflection. Increasing the number of interpolation knots reduced the errors, however, it caused overfitting in the other regions. Although significant speed-up was not observed in the univariate interpolation, cubic spline suffered from a drastic slowdown in higher dimensions with up to 103 in 3D and 105 in 4D interpolations. The same results applied to the classical molecular dynamics simulations with FEARCF with a speed-up of up to 103 when B-spline interpolation was implemented. To conclude, the B-spline interpolation method can enhance the efficiency of the free energy calculations where cubic spline interpolation has been the currently-used method

Cation binding to 15-TBA quadruplex DNA is a multiple-pathway cation-dependent process

A combination of explicit solvent molecular dynamics simulation (30 simulations reaching 4 µs in total), hybrid quantum mechanics/molecular mechanics approach and isothermal titration calorimetry was used to investigate the atomistic picture of ion binding to 15-mer thrombin-binding quadruplex DNA (G-DNA) aptamer. Binding of ions to G-DNA is complex multiple pathway process, which is strongly affected by the type of the cation. The individual ion-binding events are substantially modulated by the connecting loops of the aptamer, which play several roles. They stabilize the molecule during time periods when the bound ions are not present, they modulate the route of the ion into the stem and they also stabilize the internal ions by closing the gates through which the ions enter the quadruplex. Using our extensive simulations, we for the first time observed full spontaneous exchange of internal cation between quadruplex molecule and bulk solvent at atomistic resolution. The simulation suggests that expulsion of the internally bound ion is correlated with initial binding of the incoming ion. The incoming ion then readily replaces the bound ion while minimizing any destabilization of the solute molecule during the exchange

Molecular dynamics simulations suggest that RNA three-way junctions can act as flexible RNA structural elements in the ribosome

We present extensive explicit solvent molecular dynamics analysis of three RNA three-way junctions (3WJs) from the large ribosomal subunit: the 3WJ formed by Helices 90–92 (H90–H92) of 23S rRNA; the 3WJ formed by H42–H44 organizing the GTPase associated center (GAC) of 23S rRNA; and the 3WJ of 5S rRNA. H92 near the peptidyl transferase center binds the 3′-CCA end of amino-acylated tRNA. The GAC binds protein factors and stimulates GTP hydrolysis driving protein synthesis. The 5S rRNA binds the central protuberance and A-site finger (ASF) involved in bridges with the 30S subunit. The simulations reveal that all three 3WJs possess significant anisotropic hinge-like flexibility between their stacked stems and dynamics within the compact regions of their adjacent stems. The A-site 3WJ dynamics may facilitate accommodation of tRNA, while the 5S 3WJ flexibility appears to be essential for coordinated movements of ASF and 5S rRNA. The GAC 3WJ may support large-scale dynamics of the L7/L12-stalk region. The simulations reveal that H42–H44 rRNA segments are not fully relaxed and in the X-ray structures they are bent towards the large subunit. The bending may be related to L10 binding and is distributed between the 3WJ and the H42–H97 contact

Failure Analysis of Graphene Sheets with Multiple Stone-Thrower-Wales Defects Using Molecular-Mechanics Based Nonlinear Finite Element Models

Experimental studies show that Stone-Thrower-Wales STW defects generally exist in graphene sheets GSs and these defects considerably affect the fracture strength of GSs. Thus, prediction of failure modes of GSs with STW defects is useful for design of graphene based nanomaterials. In this paper, effects of multiple STW defects on fracture behavior of GSs are investigated by employing molecular mechanics based nonlinear finite element models. The modified Morse potential is used to define the non-linear characteristic of covalent bonds between carbon atoms and geometric nonlinearity effects are considered in models. Different tilting angles of STW defects are considered in simulations. The analysis results showed that the fracture strength of GSs strongly depends on tilting angle of multiple STW defects and the STW defects cause significant strength loss in GSs. The crack initiation and propagation are also studied and brittle failure characteristics are observed for all samples. The results obtained from this study provide some insights into design of GS based-structures with multiple STW defects

Molecular Docking and Thermodynamic Studies of the Interactions between Aspirinate Complexes of Transition metals and Cyclooxygenase-2 Enzyme: Quantum Chemical Calculations based on the ONIOM method

In the present research, molecular docking and thermodynamic properties of the transition metal complexes of aspirin were calculated against Cyclooxygenase-2 (COX-2) enzyme.  Density functional theory with dispersion function (DFT-D) using LANL2DZ basis set calculation was carried out to study the structural and thermodynamic properties of the interaction between aspirinate complexes of transition metals and COX-2. The ONIOM2 (wB97X-D/LANL2DZ:UFF) method was applied to the interaction of transition metal complexes with COX-2 binding site. The Interaction enthalpies and the Gibbs free energies between aspirinate complexes of Cu(II), Zn(II), Fe(III), and In(III) as anti-inflammatory complexes and COX-2  enzyme in the gas phase were calculated. The structure as well as the thermodynamics of optimized metal complexes was debated from the biological point of view. In the gas phase, the interaction was relatively strong and transition metal complexes could be used as potential anti-inflammatory drugs.</p

Molecular Dynamics Simulation of Copper Deposition by Ion Beam Assisted Deposition and Physical Vapour Deposition Technique

Physical Vapour Deposition (PVD) is a method of thin film deposition that involves transport of materials in the gas phase through physical means. The greatest advantage of using PVD is its ability to deposit hard coatings that are almost impossible to deposit by other liquid or chemical deposition methods. The applications of PVD include semiconductor devices, cutting and drilling tools, optical coating for displays, and decorative coatings for jewellery. When PVD process is accompanied by a separate (noble) gas ion bombardment, it is termed as Ion Beam Assisted Deposition (IBAD). These two processes can be subjected to atomistic simulation as opposed to conventional experimental methods. The idea behind such a simulation is the level of control in terms of material purity, dimensionality and simulation parameters. In this simulation work, the growth and overall morphology of epitaxial growth of copper film under both PVD and IBAD is considered. The film roughness and intrinsic stress are subjected to testing under various deposition energies in PVD. The same properties are also tested under variation of bombardment energies, and bombarding rates or ion fluence in IBAD. The results show that the nature of the film growth is primarily dependent on the deposition energy. In PVD, low deposition energies lead to growth dominated by island growth, while high deposition energies are mainly layer-by-layer growth dominated. In IBAD done at a constant low atom deposition energy, a similar trend is seen with an increasing argon ion bombardment energy at 0.5 ions/nm2 fluence. Since the deposition energy of 1 eV is geared towards island growth, the conversion rate of island like structures to relatively layer-by-layer structure depends on the ion bombardment energy (IBAD case). By comparison of IBAD and PVD outcomes, it has been established that the best layered PVD film occurs at a deposition energy of 30 eV. The overall film quality (in PVD) with respect to layer-by-layer growth is much better than that deposited using IBAD at similar bombardment energy at an ion fluence 0.5 ions/nm2. However, to attain a comparable or superior layer-by-layer growth as PVD, IBAD process has to be conducted at a much higher bombardment energy (50 eV) at fluence of 0.5 ions/nm2. The other alternative is to undertake IBAD process at bombardment energy of 30 eV, and at a much higher ion fluence. At a fluence of 0.8 ions/nm2 and equivalent ion bombardment energy (30 eV) produces a far much superior structure to PVD growth. The tradeoff between which ion fluence to use in IBAD is the deposition rate. Higher ion fluence translates to slow deposition but much improved layer-by-layer structure. The stress profile shows a decreasing stress profile as a function of thickness as predicted by Stoney's equation. At non-equilibrium deposition conditions, the film is generally stressed. However, under optimal conditions for layer-by-layer growth, IBAD grown films are generally less stressed in comparison to PVD

Computational studies of mycobacterium tuberculosis L, d-transpeptidase2.

Masters Degree. University of KwaZulu-Natal, Durban.Tuberculosis (TB) is still one of the most highly elusive lethal transmittable diseases to eradicate and persist to be a major threat to public health due to emergence of drug resistance. Drug-resistant is steadily increasing worldwide, therefore, there is an urgent need for development of improved efficacious antibiotics and novel drug targets to successfully contain the disease. Peptidoglycan layer (PG) is the major attribute in bacterial cell envelope and is essential for protection and growth in all bacterial species including Mycobacterium tuberculosis(Mtb). The biosynthesis pathway for PG is extremely intricate and involves numerous interconnected metabolites such as N-acetylmuramic(NAM) acid and N-acetylglucosamine(NAG), that are required during transpeptidation. These two sugar molecules are linked together by a β (1-4) glycosidic bond and the NAM attaches 3-5 amino acid peptide stems. Consequently, the peptidoglycan strands are cross linked by transpeptidases, namely D, D- and L, D-transpeptidases, forming crucial 4→3 and 3→3 cross-linkages respectively. Both D, D- and L, D-transpeptidases need to be inhibited concomitantly to eradicate the bacterium. L, D-transpeptidase 2 (LdtMt2) is one of the paralogs that is essential for Mtb growth, cell morphology and virulence during the chronic stage of the disease. This paralog has major influence in drug resistance and persistence of tuberculosis. The traditional β-lactam family of antibiotics have been reported to be effective against Mtb following the inactivation of β-lactamases (BlaC) known to rapidly hydrolyze the core β-lactam ring. The classic penicillins inhibit D, D-transpeptidases, while L, D transpeptidases are blocked by carbapenems. Despite several studies in this field, to the best of our knowledge, limited attention has been paid to the inhibition mechanism of LdtMt2 using carbapenem derivatives. In this regard, we need to explore reliable alternative strategies that are most cost-effective in terms of investigating the interactions of FDA approved carbapenems against Mtb L, D-Transpeptidases and study the role of explicit water molecule confined in the active site. As a result, computational chemistry has provided the possibility to sightsee and investigate this problem with relatively cost effective computational techniques. In this thesis, we applied a hybrid quantum mechanics and molecular mechanics techniques (QM:MM), Our own N-layered Integrated molecular Orbital and Molecular Mechanics (ONIOM) approach, to investigate the binding interaction energies of carbapenems (biapenem, imipenem, meropenem and tebipenem) against L, D-transpeptidase 2. Furthermore, the role of explicit water molecule confined in the active site was also explored using the same hybrid method to ascertain the nature of binding interaction energies of carbapenems against LdtMt2. In all the investigated carbapenem─LdtMt2 complexes, the carbapenems and the catalytic active site residues of LdtMt2 (Cys205, His187, Ser188, His203 and Asn207) were treated at QM (B3LYP/6-31+G(d)) level of theory whereas the remaining part of the complexes were treated at MM level (AMBER force field). The explicit water molecules near the carbapenems were considered and treated at QM as well. The obtained findings of Gibbs free energy (G), enthalpy (H) and entropy (S) for all studied complexes showed that the carbapenems exhibit reasonable binding interactions towards LdtMt2. This can be attributed by the structural dissimilarities of the carbapenems side chain which significantly induce conformational changes in the LdtMt2. In comparison, the binding free energy calculations of the model system with explicit water molecule yielded significant binding interaction energies. The QTAIM and NBO results confirmed the nature of binding free energies that the topological properties of atoms in molecules and the delocalization of electrons are from a bonding to antibonding orbitals in hydrogen bond interactions and this has enhanced the stability of carbapenem―LdtMt2 complexes. We believe that molecular insight of the carbapenems binding to LdtMt2 and the role of explicit solvent will enable us to understand the inhibition mechanisms