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    ABSTRACT: Accurately representing molecules with many coupled unpaired electrons is currently impossible using conventional electronic-structure theories. Now, using a recently developed approach, the near-exact quantum wavefunction of the highly complex Mn4CaO5 cluster of photosystem II has been calculated.
    Nature Chemistry 08/2013; 5(8):643-4.
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    ABSTRACT: We present a method that accurately describes strongly correlated states and captures dynamical correlation. It is derived as a modification of coupled-cluster theory with single and double excitations (CCSD) through consideration of particle distinguishability between dissociated fragments, whilst retaining the key desirable properties of particle-hole symmetry, size extensivity, invariance to rotations within the occupied and virtual spaces, and exactness for two-electron subsystems. The resulting method, called the distinguishable cluster approximation, smoothly dissociates difficult cases such as the nitrogen molecule, with the modest N(6) computational cost of CCSD. Even for molecules near their equilibrium geometries, the new model outperforms CCSD. It also accurately describes the massively correlated states encountered when dissociating hydrogen lattices, a proxy for the metal-insulator transition, and the fully dissociated system is treated exactly.
    The Journal of Chemical Physics 07/2013; 139(2):021102.
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    ABSTRACT: Ketosteroid isomerase (Δ(5) -3-keto steroid isomerase or steroid Δ-isomerase) is a highly efficient enzyme at the centre of current debates on enzyme catalysis. We have modeled the reaction mechanism of the isomerisation of 3-oxo-Δ(5) -steroids into their Δ(4) -conjugated isomers using high-level combined quantum mechanics/molecular mechanics (QM/MM) methods, and semi-empirical QM/MM molecular dynamics simulations. Energy profiles were obtained at different levels of QM theory (AM1, B3LYP and SCS-MP2). The high-level QM/MM profile is consistent with experimental data. QM/MM dynamics simulations indicate that active site closure and desolvation of the catalytic Asp38 occur before or during dienolate intermediate formation. These changes are shown to have a significant effect on the reaction barrier. A low barrier to reaction is found only when the active site is closed, poising it for catalysis. This conformational change is thus integral to the whole process. The effects on the barrier are apparently largely due to changes in solvation. The combination of high-level QM/MM energy profiles and QM/MM dynamics simulation shows that the reaction involves active site closure, desolvation of the catalytic base, efficient isomerisation and reopening of the active site. These changes highlight the transition between the ligand binding/releasing form and the catalytic form of the enzyme. The results demonstrate that electrostatic interactions (as a consequence of pre-organisation of the active site) are crucial for stabilisation during the chemical reaction step, but closure of the active site is essential for efficient catalysis to occur. © 2013 The Authors Journal compilation © 2013 FEBS.
    FEBS Journal 01/2013;
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    ABSTRACT: Reliable prediction of molecular crystal energetics is a vital goal for computational chemistry. Here we show that accurate results can be obtained from a monomer-based many-body expansion truncated at the two-body level, with the monomer and dimer calculations suitably embedded in a model of the crystalline environment. By including the two dominant effects-electrostatics and exchange-repulsion-we are able to capture the important nonadditive terms in the energy, and approach very closely results from full periodic second-order Mo̸ller-Plesset calculations. The advantage of the current scheme is that extension to coupled-cluster and explicitly correlated F12 methods is completely straightforward. We demonstrate the approach through calculations on carbon dioxide, hydrogen fluoride, and ice XIh and XIc. In accord with previous studies, we find these two ice polymorphs to be very close in energy, with our periodic coupled-cluster single double triple-F12 calculation giving the hexagonal structure more stable by around 0.3 kJ mol(-1).
    The Journal of Chemical Physics 10/2012; 137(16):164102.
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    ABSTRACT: One of the most controversial questions in enzymology today is whether protein dynamics are significant in enzyme catalysis. A particular issue in these debates is the unusual temperature-dependence of some kinetic isotope effects for enzyme-catalysed reactions. In the present paper, we review our recent model [Glowacki, Harvey and Mulholland (2012) Nat. Chem. 4, 169-176] that is capable of reproducing intriguing temperature-dependences of enzyme reactions involving significant quantum tunnelling. This model relies on treating multiple conformations of the enzyme-substrate complex. The results show that direct 'driving' motions of proteins are not necessary to explain experimental observations, and show that enzyme reactivity can be understood and accounted for in the framework of transition state theory.
    Biochemical Society Transactions 06/2012; 40(3):515-21.
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    ABSTRACT: Multidrug resistance of the pandemic H1N1-2009 strain of influenza has been reported due to widespread treatment using the neuraminidase (NA) inhibitors, oseltamivir (Tamiflu), and zanamivir (Relenza). From clinical data, the single I223R (IR(1)) mutant of H1N1-2009 NA reduced efficacy of oseltamivir and zanamivir by 45 and 10 times, (1) respectively. More seriously, the efficacy of these two inhibitors against the double mutant I223R/H275Y (IRHY(2)) was significantly reduced by a factor of 12 374 and 21 times, respectively, compared to the wild-type.(2) This has led to the question of why the efficacy of the NA inhibitors is reduced by the occurrence of these mutations and, specifically, why the efficacy of oseltamivir against the double mutant IRHY was significantly reduced, to the point where oseltamivir has become an ineffective treatment. In this study, 1 μs of molecular dynamics (MD) simulations was performed to answer these questions. The simulations, run using graphical processors (GPUs), were used to investigate the effect of conformational change upon binding of the NA inhibitors oseltamivir and zanamivir in the wild-type and the IR and IRHY mutant strains. These long time scale dynamics simulations demonstrated that the mechanism of resistance of IRHY to oseltamivir was due to the loss of key hydrogen bonds between the inhibitor and residues in the 150-loop. This allowed NA to transition from a closed to an open conformation. Oseltamivir binds weakly with the open conformation of NA due to poor electrostatic interactions between the inhibitor and the active site. The results suggest that the efficacy of oseltamivir is reduced significantly because of conformational changes that lead to the open form of the 150-loop. This suggests that drug resistance could be overcome by increasing hydrogen bond interactions between NA inhibitors and residues in the 150-loop, with the aim of maintaining the closed conformation, or by designing inhibitors that can form a hydrogen bond to the mutant R223 residue, thereby preventing competition between R223 and R152.
    Biochemistry 05/2012; 51(21):4364-75.
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    ABSTRACT: We show that the quality of density functional theory (DFT) predictions for the relative stabilities of polymorphs of crystalline para-diiodobenzene (PDIB) is dramatically improved through a simple two-body correction using wavefunction-based electronic structure theory. PDIB has two stable polymorphs under ambient conditions, and like Hongo et al. [J. Phys. Chem. Lett., 1, 1789 (2010)] we find that DFT makes wildly variable predictions of the relative stabilities, depending on the approximate functional used. The two-body corrected scheme, using Grimme's spin-scaled variant of second-order Møller-Plesset perturbation theory and any of the tested density functionals, predicts the α-polymorph to be more stable, consistent with experiment, and produces a relative stability that agrees with the benchmark quantum Monte-Carlo results of Hongo et al. within statistical uncertainty.
    Physical Chemistry Chemical Physics 03/2012; 14(21):7739-43.
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    ABSTRACT: Soluble epoxide hydrolase (sEH) is an enzyme involved in drug metabolism that catalyzes the hydrolysis of epoxides to form their corresponding diols. sEH has a broad substrate range and shows high regio- and enantioselectivity for nucleophilic ring opening by Asp333. Epoxide hydrolases therefore have potential synthetic applications. We have used combined quantum mechanics/molecular mechanics (QM/MM) umbrella sampling molecular dynamics (MD) simulations (at the AM1/CHARMM22 level) and high-level ab initio (SCS-MP2) QM/MM calculations to analyze the reactions, and determinants of selectivity, for two substrates: trans-stilbene oxide (t-SO) and trans-diphenylpropene oxide (t-DPPO). The calculated free energy barriers from the QM/MM (AM1/CHARMM22) umbrella sampling MD simulations show a lower barrier for phenyl attack in t-DPPO, compared with that for benzylic attack, in agreement with experiment. Activation barriers in agreement with experimental rate constants are obtained only with the highest level of QM theory (SCS-MP2) used. Our results show that the selectivity of the ring-opening reaction is influenced by several factors, including proximity to the nucleophile, electronic stabilization of the transition state, and hydrogen bonding to two active site tyrosine residues. The protonation state of His523 during nucleophilic attack has also been investigated, and our results show that the protonated form is most consistent with experimental findings. The work presented here illustrates how determinants of selectivity can be identified from QM/MM simulations. These insights may also provide useful information for the design of novel catalysts for use in the synthesis of enantiopure compounds.
    Biochemistry 02/2012; 51(8):1774-86.
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    ABSTRACT: We propose an approach to modelling multidimensional quantum systems which uses direct-dynamics trajectories to guide wavefunction propagation. First, trajectory simulations are used to generate a sample of dynamically relevant configurations on the potential energy surface (PES). Second, the sampled configurations are used to construct an n-mode representation of the PES using a greedy algorithm. Finally, the time-dependent Schrödinger equation is solved using a configuration interaction expansion of the wavefunction, with individual basis functions derived directly from the 1-mode contributions to the n-mode PES. This approach is successfully demonstrated by application to a 20-dimensional benchmark problem describing tunnelling in the presence of coupled degrees of freedom.
    The Journal of Chemical Physics 02/2012; 136(5):054109.
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    ABSTRACT: Molecular modelling and simulation methods are increasingly at the forefront of elucidating mechanisms of enzyme-catalysed reactions, and shedding light on the determinants of specificity and efficiency of catalysis. These methods have the potential to assist in drug discovery and the design of novel protein catalysts. This Tutorial Review highlights some of the most widely used modelling methods and some successful applications. Modelling protocols commonly applied in studying enzyme-catalysed reactions are outlined here, and some practical implications are considered, with cytochrome P450 enzymes used as a specific example.
    Chemical Society Reviews 01/2012; 41(8):3025-38.
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