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  • 1. Asgari, Parham
    et al.
    Hua, Yuanda
    Bokka, Apparao
    Thiamsiri, Chanachon
    Prasitwatcharakorn, Watcharapon
    Karedath, Ashif
    Chen, Xin
    Sardar, Sinjinee
    Yum, Kyungsuk
    Leem, Gyu
    Pierce, Brad S.
    Nam, Kwangho
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Gao, Jiali
    Jeon, Junha
    Catalytic hydrogen atom transfer from hydrosilanes to vinylarenes for hydrosilylation and polymerization2019Ingår i: Nature Catalysis, ISSN 2520-1158, Vol. 2, nr 2, s. 164-173Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Because of the importance of hydrogen atom transfer (HAT) in biology and chemistry, there is increased interest in new strategies to perform HAT in a sustainable manner. Here, we describe a sustainable, net redox-neutral HAT process involving hydrosilanes and alkali metal Lewis base catalysts-eliminating the use of transition metal catalysts-and report an associated mechanism concerning Lewis base-catalysed, complexation-induced HAT. The catalytic Lewis base-catalysed, complexation-induced HAT is capable of accessing both branch-specific hydrosilylation and polymerization of vinylarenes in a highly selective fashion, depending on the Lewis base catalyst used. In this process, the Earth-abundant, alkali metal Lewis base catalyst plays a dual role. It first serves as a HAT initiator and subsequently functions as a silyl radical stabilizing group, which is critical to highly selective cross-radical coupling. An electron paramagnetic resonance study identified a potassiated paramagnetic species, and multistate density functional theory revealed a high HAT character, yet multiconfigurational nature in the transition state of the reaction.

  • 2. Das, Susanta
    et al.
    Nam, Kwangho
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen. Department of Chemistry and Biochemistry, University of Texas at Arlington, United States.
    Major, Dan Thomas
    Rapid Convergence of Energy and Free Energy Profiles with Quantum Mechanical Size in Quantum Mechanical–Molecular Mechanical Simulations of Proton Transfer in DNA2018Ingår i: Journal of Chemical Theory and Computation, ISSN 1549-9618, E-ISSN 1549-9626, Vol. 14, nr 3, s. 1695-1705Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    In recent years, a number of quantum mechanical-molecular mechanical (QM/MM) enzyme studies have investigated the dependence of reaction energetics on the size of the QM region using energy and free energy calculations. In this study, we revisit the question of QM region size dependence in QM/MM simulations within the context of energy and free energy calculations using a proton transfer in a DNA base pair as a test case. In the simulations, the QM region was treated with a dispersion-corrected AM1/d-PhoT Hamiltonian, which was developed to accurately describe phosphoryl and proton transfer reactions, in conjunction with an electrostatic embedding scheme using the particle-mesh Ewald summation method. With this rigorous QM/MM potential, we performed rather extensive QM/MM sampling, and found that the free energy reaction profiles converge rapidly with respect to the QM region size within ca. +/- 1 kcal/mol. This finding suggests that the strategy of QM/MM simulations with reasonably sized and selected QM regions, which has been employed for over four decades, is a valid approach for modeling complex biomolecular systems. We point to possible causes for the sensitivity of the energy and free energy calculations to the size of the QM region, and potential implications.

  • 3. Doron, Dvir
    et al.
    Kohen, Amnon
    Nam, Kwangho
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Major, Dan Thomas
    How Accurate Are Transition States from Simulations of Enzymatic Reactions?2014Ingår i: Journal of Chemical Theory and Computation, ISSN 1549-9618, E-ISSN 1549-9626, Vol. 10, nr 5, s. 1863-1871Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The rate expression of traditional transition state theory (TST) assumes no recrossing of the transition state (TS) and thermal quasi-equilibrium between the ground state and the TS. Currently, it is not well understood to what extent these assumptions influence the nature of the activated complex obtained in traditional TST-based simulations of processes in the condensed phase in general and in enzymes in particular. Here we scrutinize these assumptions by characterizing the TSs for hydride transfer catalyzed by the enzyme Escherichia coli dihydrofolate reductase obtained using various simulation approaches. Specifically, we compare the TSs obtained with common TST-based methods and a dynamics-based method. Using a recently developed accurate hybrid quantum mechanics/molecular mechanics potential, we find that the TST-based and dynamics-based methods give considerably different TS ensembles. This discrepancy, which could be due equilibrium solvation effects and the nature of the reaction coordinate employed and its motion, raises major questions about how to interpret the TSs determined by common simulation methods. We conclude that further investigation is needed to characterize the impact of various TST assumptions on the TS phase-space ensemble and on the reaction kinetics.

  • 4.
    Huang, Yang
    et al.
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Nam, Kwangho
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Westlund, Per-Olof
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    The water R1(ω) NMRD profiles of a hydrated protein from molecular dynamics simulation2013Ingår i: Physical Chemistry, Chemical Physics - PCCP, ISSN 1463-9076, E-ISSN 1463-9084, Vol. 15, nr 33, s. 14089-14097Artikel i tidskrift (Refereegranskat)
    Abstract [en]

     The hydration of a protein, peroxiredoxin 5, is obtained from a molecular dynamics simulation and compared with the picture of hydration which is obtained by analysing the water proton R1 NMRD profiles using a generally accepted relaxation model [K. Venu, V.P. Denisov and B. Halle, J. Am. Chem. Soc. 119,3122(1997)]. The discrepancy between the hydration pictures derived from the water R1 0)-NMRD profiles and MD is relevant in a discussion of the factors behind the stretched NMRD profile, the distribution of orientationalorder parameters and residence times of buried water used in the NMRD model.

  • 5. Koag, Myong-Chul
    et al.
    Nam, Kwangho
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Lee, Seongmin
    The spontaneous replication error and the mismatch discrimination mechanisms of human DNA polymerase beta2014Ingår i: Nucleic Acids Research, ISSN 0305-1048, E-ISSN 1362-4962, Vol. 42, nr 17, s. 11233-11245Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    To provide molecular-level insights into the spontaneous replication error and the mismatch discrimination mechanisms of human DNA polymerase beta (pol beta), we report four crystal structures of pol beta complexed with dG.dTTP and dA.dCTP mismatches in the presence of Mg2+ or Mn2+. The Mg2+-bound ground-state structures show that the dA.dCTP-Mg2+ complex adopts an 'intermediate' protein conformation while the dG.dTTP-Mg2+ complex adopts an open protein conformation. The Mn2+-bound 'pre-chemistry-state' structures show that the dA.dCTP-Mn2+ complex is structurally very similar to the dA.dCTP-Mg2+ complex, whereas the dG.dTTP-Mn2+ complex undergoes a large-scale conformational change to adopt a Watson-Crick-like dG.dTTP base pair and a closed protein conformation. These structural differences, together with our molecular dynamics simulation studies, suggest that pol beta increases replication fidelity via a two-stage mismatch discrimination mechanism, where one is in the ground state and the other in the closed conformation state. In the closed conformation state, pol beta appears to allow only a Watson-Crick-like conformation for purine.pyrimidine base pairs, thereby discriminating the mismatched base pairs based on their ability to form the Watson-Crick-like conformation. Overall, the present studies provide new insights into the spontaneous replication error and the replication fidelity mechanisms of pol beta.

  • 6.
    Li, Yaozong
    et al.
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Nam, Kwangho
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen. Univ Texas Arlington, Dept Chem & Biochem, Arlington, TX 76019 USA.
    Dynamic, structural and thermodynamic basis of insulin-like growth factor 1 kinase allostery mediated by activation loop phosphorylation2017Ingår i: Chemical Science, ISSN 2041-6539, Vol. 8, nr 5, s. 3453-3464Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Despite the importance of kinases' catalytic activity regulation in cell signaling, detailed mechanisms underlying their activity regulation are poorly understood. Herein, using insulin-like growth factor 1 receptor kinase (IGF-1RK) as a model, the mechanisms of kinase regulation by its activation loop (A-loop) phosphorylation were investigated through molecular dynamics (MD) and alchemical free energy simulations. Analyses of the simulation results and free energy landscapes determined for the entire catalytic cycle of the kinase revealed that A-loop phosphorylation affects each step in the IGF-1RK catalytic cycle, including conformational change, substrate binding/product release and catalytic phosphoryl transfer. Specifically, the conformational equilibrium of the kinase is shifted by 13.2 kcal mol−1 to favor the active conformation after A-loop phosphorylation, which increases substrate binding affinity of the activated kinase. This free energy shift is achieved primarily viadestabilization of the inactive conformation. The free energy of the catalytic reaction is also changed by 3.3 kcal mol−1 after the phosphorylation and in the end, facilitates product release. Analyses of MD simulations showed that A-loop phosphorylation produces these energetic effects by perturbing the side chain interactions around each A-loop tyrosine. These interaction changes are propagated to the remainder of the kinase to modify the orientations and dynamics of the αC-helix and A-loop, and together yield the observed free energy changes. Since many protein kinases share similar interactions identified in this work, the mechanisms of kinase allostery and catalysis unraveled here can be applicable to them.

  • 7.
    Li, Yaozong
    et al.
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Nam, Kwangho
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Physical end-point extrapolatable soft-core potentials for efficient and accurate alchemical free energy calculationsManuskript (preprint) (Övrigt vetenskapligt)
  • 8.
    Liem-Nguyen, Van
    et al.
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Skyllberg, Ulf
    Nam, Kwangho
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Bjoern, Erik
    Thermodynamic stability of mercury(II) complexes formed with environmentally relevant low-molecular-mass thiols studied by competing ligand exchange and density functional theory2017Ingår i: Environmental Chemistry, ISSN 1448-2517, E-ISSN 1449-8979, Vol. 14, nr 4, s. 243-253Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Inorganic divalent mercury (Hg-II) has a very high affinity for reduced sulfur functional groups. Reports from laboratory experiments suggest that Hg-II complexes with specific low-molecular-mass (LMM) thiol (RSH) ligands control rates of Hg-II transformation reactions. Because of methodological limitations for precise determination of the highly stable Hg-II complexes with LMM thiol ligands, constants reported in the literature remain inconsistent. This uncertainty impedes accurate modelling of the chemical speciation of Hg-II and the possibility to elucidate the role of Hg-II complexes with LMM thiols for Hg transformation reactions. Here, we report values of thermodynamic stability constants for 15 monodentate, two-coordinated Hg-II complexes, Hg(SR)(2), formed with biogeochemically relevant LMM thiol ligands. The constants were determined by a two-step ligand-exchange procedure where the specific Hg(SR)(2) complexes were quantified by liquid chromatography-inductively coupled plasma mass spectrometry. Thermodynamic stability constants (log (2)) determined for the Hg(SR)(2) complexes ranged from 34.6, N-cysteinylglycine, to 42.1, 3-mercaptopropionic acid, for the general reaction Hg2++2RS(-) Hg(SR)(2). Density functional theory (DFT) calculations showed that electron-donating carboxyl and carbonyl groups have a stabilising effect on the Hg-II-LMM thiol complexes, whereas electron-withdrawing protonated primary amino groups have a destabilising effect. Experimental results and DFT calculations demonstrated that the presence of such functional groups in the vicinity of the RSH group caused significant differences in the stability of Hg(SR)(2) complexes. These differences are expected to be important for the chemical speciation of Hg-II and its transformation reactions in environments where a multitude of LMM thiol compounds are present.

  • 9.
    Mishra, Yogesh
    et al.
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen. Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Umeå Plant Science Centre (UPSC).
    Hall, Michael
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Locmelis, Roland
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Nam, Kwangho
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen. Department of Chemistry and Biochemistry, University of Texas at Arlington, Arlington, TX, 76019-0065, USA.
    Söderberg, Christopher A. G.
    Storm, Patrik
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Chaurasia, Neha
    Rai, Lal Chand
    Jansson, Stefan
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Umeå Plant Science Centre (UPSC). Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Institutionen för fysiologisk botanik.
    Schröder, Wolfgang P.
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen. Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Umeå Plant Science Centre (UPSC).
    Sauer, Uwe H.
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Active-site plasticity revealed in the asymmetric dimer of AnPrx6 the 1-Cys peroxiredoxin and molecular chaperone from Anabaena sp. PCC 71202017Ingår i: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 7, artikel-id 17151Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Peroxiredoxins (Prxs) are vital regulators of intracellular reactive oxygen species levels in all living organisms. Their activity depends on one or two catalytically active cysteine residues, the peroxidatic Cys (C-P) and, if present, the resolving Cys (C-R). A detailed catalytic cycle has been derived for typical 2-Cys Prxs, however, little is known about the catalytic cycle of 1-Cys Prxs. We have characterized Prx6 from the cyanobacterium Anabaena sp. strain PCC7120 (AnPrx6) and found that in addition to the expected peroxidase activity, AnPrx6 can act as a molecular chaperone in its dimeric state, contrary to other Prxs. The AnPrx6 crystal structure at 2.3 angstrom resolution reveals different active site conformations in each monomer of the asymmetric obligate homo-dimer. Molecular dynamic simulations support the observed structural plasticity. A FSH motif, conserved in 1-Cys Prxs, precedes the active site PxxxTxxCp signature and might contribute to the 1-Cys Prx reaction cycle.

  • 10.
    Nam, Kwangho
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Acceleration of Ab Initio QM/MM Calculations under Periodic Boundary Conditions by Multiscale and Multiple Time Step Approaches2014Ingår i: Journal of Chemical Theory and Computation, ISSN 1549-9618, E-ISSN 1549-9626, Vol. 10, nr 10, s. 4175-4183Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Development of multiscale ab initio quantum mechanical and molecular mechanical (AI-QM/MM) method for periodic boundary molecular dynamics (MD) simulations and their acceleration by multiple time step approach are described. The developed method achieves accuracy and efficiency by integrating the AI-QM/MM level of theory and the previously developed semiempirical (SE) QM/MM-Ewald sum method [J. Chem. Theory Comput. 2005, 1, 2] extended to the smooth particle-mesh Ewald (PME) summation method. In the developed methods, the total energy of the simulated system is evaluated at the SE-QM/MM-PME level of theory to include long-range QM/MM electrostatic interactions, which is then corrected on the fly using the AI-QM/MM level of theory within the real space cutoff. The resulting energy expression enables decomposition of total forces applied to each atom into forces determined at the low-level SE-QM/MM method and correction forces at the AI-QM/MM level, to integrate the system using the reversible reference system propagator algorithm. The resulting method achieves a substantial speed-up of the entire calculation by minimizing the number of time-consuming energy and gradient evaluations at the AI-QM/MM level. Test calculations show that the developed multiple time step AI-QM/MM method yields MD trajectories and potential of mean force profiles comparable to single time step QM/MM results. The developed method, together with message passing interface (MPI) parallelization, accelerates the present AI-QM/MM MD simulations about 30-fold relative to the speed of single-core AI-QM/MM simulations for the molecular systems tested in the present work, making the method less than one order slower than the SE-QM/MM methods under periodic boundary conditions.

  • 11.
    Nam, Kwangho
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Acceleration of Semiempirical Quantum Mechanical Calculations by Extended Lagrangian Molecular Dynamics Approach2013Ingår i: Journal of Chemical Theory and Computation, ISSN 1549-9618, E-ISSN 1549-9626, Vol. 9, nr 8, s. 3393-3403Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The implementation and performance of the atom-centered density matrix propagation (ADMP) [J. Chem. Phys. 2001, 114, 9758] and the curvy-steps (CURV) methods [J. Chem. Phys. 2004, 121, 1152] are described. These methods solve the electronic Schrodinger equation approximately by propagating the electronic degrees of freedom using the extended Lagrangian molecular dynamics (ELMD) simulation approach. The ADMP and CURV methods are implemented and parallelized to accelerate semiempirical quantum mechanical (QM) methods (such as the MNDO, AM1, PM3, MNDO/d, and AM1/d methods). Test calculations show that both the ADMP and the CURV methods are 2 similar to 4 times faster than the Born-Oppenheimer molecular dynamics (BOMD) method and conserve the total energy well. The accuracy of the ADMP and CURV simulations is comparable to the BOMD simulations. The parallel implementation accelerates the MD simulation by up to 28 fold for the ADMP method and 25 fold for the CURV method, respectively, relative to the speed of the single core BOMD. In addition, a multiple time scale (MTS) approach is introduced to further speed up the semiempirical QM and QM/MM ELMD simulations. Since a larger integration time step is used for the propagation of the nuclear coordinates than that for the electronic degrees of freedom, the MTS approach allows the ELMD simulation to be carried out with a time step that is larger than the time step accessible by the original ADMP and CURV methods. It renders MD simulation to be carried out about 20 times faster than the BOMD simulation, and yields results that are comparable to the single time scale simulation results. The use of the methods introduced in the present work provides an efficient way to extend the length of the QM and QM/MM molecular dynamics simulations beyond the length accessible by BOMD simulation.

  • 12.
    Nam, Kwangho
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Development of multi-scale QM/MM methods for studying the reaction catalyzed by protein tyrosine kinase2014Ingår i: Abstract of Papers of the American Chemical Society, ISSN 0065-7727, Vol. 248Artikel i tidskrift (Övrigt vetenskapligt)
  • 13.
    Nam, Kwangho
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen. University of Texas at Arlington, Department of Chemistry & Biochemistry, Arlington, TX 76019 USA.
    New repulsive soft-core potential for accelerated alchemical free energy calculations2017Ingår i: Abstract of Papers of the American Chemical Society, ISSN 0065-7727, Vol. 254Artikel i tidskrift (Övrigt vetenskapligt)
  • 14.
    Nam, Kwangho
    et al.
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen. Department of Chemistry and Chemical Biology, Harvard University, Cambridge.
    Pu, Jingzhi
    Karplus, Martin
    Trapping the ATP binding state leads to a detailed understanding of the F-1-ATPase mechanism2014Ingår i: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 111, nr 50, s. 17851-17856Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The rotary motor enzyme FoF1-ATP synthase uses the protonmotive force across a membrane to synthesize ATP from ADP and P-i (H2PO4-) under cellular conditions that favor the hydrolysis reaction by a factor of 2 x 10(5). This remarkable ability to drive a reaction away from equilibrium by harnessing an external force differentiates it from an ordinary enzyme, which increases the rate of reaction without shifting the equilibrium. Hydrolysis takes place in the neighborhood of one conformation of the catalytic moiety F-1-ATPase, whose structure is known from crystallography. By use of molecular dynamics simulations we trap a second structure, which is rotated by 40 degrees from the catalytic dwell conformation and represents the state associated with ATP binding, in accord with single-molecule experiments. Using the two structures, we show why Pi is not released immediately after ATP hydrolysis, but only after a subsequent 120 degrees rotation, in agreement with experiment. A concerted conformational change of the alpha(3)beta(3) crown is shown to induce the 40 degrees rotation of the gamma-subunit only when the beta(E) subunit is empty, whereas with Pi bound, beta(E) serves as a latch to prevent the rotation of gamma. The present results provide a rationalization of how F-1-ATPase achieves the coupling between the small changes in the active site of beta(DP) and the 40 degrees rotation of gamma.

  • 15. Nestor, Stephen T.
    et al.
    Hawkins, Allison N.
    Xhani, Xhensila
    Sykora, Richard E.
    Mao, James X.
    Nam, Kwangho
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen. Department of Chemistry and Biochemistry, University of Texas at Arlington, Arlington, Texas, United States.
    McManus, Gregory J.
    Mirjafari, Arsalan
    Studies on solubility and S-alkylation of 2-thiouracil in ionic liquids2018Ingår i: Journal of Molecular Liquids, ISSN 0167-7322, E-ISSN 1873-3166, Vol. 265, s. 463-467Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Ionic liquids have been exploited to assist dissolution of poorly soluble (and poorly bioavailable) drugs, enhancing permeation through physiological barriers to deliver drugs to target sites. Herein, the solubility of 6-methyl-2-thiouracil - a common antithyroid drug, with low solubility in water and common organic solvents- was studied by employing six different imidazolium-based ionic liquids with variable anions. We demonstrate facile, regiospecific S-alkylation of 2-thiouracil with various lipophilic side chains in high yields (91-94%) and in the absence of catalysts. The reaction yields are correlated with the H-bond formation ability between the ILs' anions and the solute, indicating that the hydrogen bond is perhaps responsible for the high solubility of 2-thiouracil in [C(2)mim][OAc] and [C(2)mim][Cl]. 

  • 16.
    Nilsson, Lina
    et al.
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Ådén, Jörgen
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Niemiec, Moritz S.
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Nam, Kwangho
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen. Computational Life Science Center (CLiC), Umeå University,.
    Wittung-Stafshede, Pernilla
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Small pH and Salt Variations Radically Alter the Thermal Stability of Metal-Binding Domains in the Copper Transporter, Wilson Disease Protein2013Ingår i: Journal of Physical Chemistry B, ISSN 1520-6106, E-ISSN 1520-5207, Vol. 117, nr 42, s. 13038-13050Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Although strictly regulated, pH and solute concentrations in cells may exhibit temporal and spatial fluctuations. Here we study the effect of such changes on the stability, structure, and dynamics in vitro and in silico of a two-domain construct (WD56) of the fifth and sixth metal-binding domains of the copper transport protein, ATP7B (Wilson disease protein). We find that the thermal stability of WD56 is increased by 40 °C when increasing the pH from 5.0 to 7.5. In contrast, addition of salt at pH 7.2 decreases WD56 stability by up to 30 °C. In agreement with domain-domain coupling, fractional copper loading increases the stability of both domains. HSQC chemical shift changes demonstrate that, upon lowering the pH from 7.2 to 6, both His in WD6 as well as the second Cys of the copper site in each domain become protonated. MD simulations reveal increased domain-domain fluctuations at pH 6 and in the presence of high salt concentration, as compared to at pH 7 and low salt concentration. Thus, the surface charge distribution at high pH contributes favorably to overall WD56 stability. By introducing more positive charges by lowering the pH, or by diminishing charge-charge interactions by salt, fluctuations among the domains are increased and thereby overall stability is reduced. Copper transfer activity also depends on pH: delivery of copper from chaperone Atox1 to WD56 is more efficient at pH 7.2 than at pH 6 by a factor of 30. It appears that WD56 is an example where the free energy landscapes for folding and function are linked via structural stability.

  • 17.
    Ojeda-May, Pedro
    et al.
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen. Computational Life Science Cluster (CLiC).
    Li, Yaozong
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen. Computational Life Science Cluster (CLiC).
    Ovchinnikov, Victor
    Nam, Kwangho
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen. Computational Life Science Cluster (CLiC).
    Role of Protein Dynamics in Allosteric Control of the Catalytic Phosphoryl Transfer of Insulin Receptor Kinase2015Ingår i: Journal of the American Chemical Society, ISSN 0002-7863, E-ISSN 1520-5126, Vol. 137, nr 39, s. 12454-12457Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The catalytic and allosteric mechanisms of insulin receptor kinase (IRK) are investigated by a combination of ab initio and semiempirical quantum mechanical and molecular mechanical (QM/MM) methods and classical molecular dynamics (MD) simulations. The simulations reveal that the catalytic reaction proceeds in two steps, starting with the transfer of a proton from substrate Tyr to the catalytic Asp1132, followed by the phosphoryl transfer from ATP to substrate Tyr. The enhancement of the catalytic rate of IRK upon phosphorylations in the enzyme's activation loop is found to occur mainly via changes to the free energy landscape of the proton transfer step, favoring the proton transfer in the fully phosphorylated enzyme. In contrast, the effects of the phosphorylations on the phosphoryl transfer are smaller. Equilibrium MD simulations show that IRK phosphorylations affect the protein dynamics of the enzyme before the proton transfer to Asp1132 with only a minor effect after the proton transfer. This finding is consistent with the large change in the proton transfer free energy and the smaller change in the free energy barrier of phosphoryl transfer found by QM/MM simulations. Taken together, the present results provide details on how IRK phosphorylation exerts allosteric control of the catalytic activity via modifications of protein dynamics and free energy landscape of catalytic reaction. The results also highlight the importance of protein dynamics in connecting protein allostery and catalysis to control catalytic activity of enzymes.

  • 18.
    Ojeda-May, Pedro
    et al.
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Högpresterande beräkningscentrum norr (HPC2N). Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Nam, Kwangho
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen. Department of Chemistry and Biochemistry, University of Texas at Arlington, Arlington, Texas 76019-0065, United States.
    Acceleration of Semiempirical QM/MM Methods through Message Passage Interface (MPI), Hybrid MPI/Open Multiprocessing, and Self-Consistent Field Accelerator Implementations2017Ingår i: Journal of Chemical Theory and Computation, ISSN 1549-9618, E-ISSN 1549-9626, Vol. 13, nr 8, s. 3525-3536Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The strategy and implementation of scalable and efficient semiempirical (SE) QM/MM methods in. CHARMM are described. The serial version of the code was first profiled to identify routines that required parallelization. Afterward, the code was parallelized and accelerated with three approaches. The first approach was the parallelization of the entire QM/MM routines, including the Fock matrix diagonalization routines, using the CHARMM message passage interface (MPI) machinery. In the second approach, two different self-consistent.field (SCF) energy convergence accelerators were implemented using density and Pock matrices as targets for their extrapolations in the SCF procedure. In the third approach, the entire QM/MM and MM energy routines were accelerated by implementing the hybrid MPI/open multiprocessing (OpenMP) model in which both the task- and loop-leveL parallelitation strategies were adopted to balance loads between different OpenMP threads. The present implementation was tested on two solvated enzyme systems (including <100 QM atoms) and an S(N)2 symmetric reaction in water. The-MPI version exceeded existing SE QM methods in CHARMM which include the SCC-DFTB and SQUANTUM methods by at least 4-fold. The use of SCF convergence accelerators further accelerated,the code by similar to 12-35% depending on the size of the QM region and the number of CPU cores used. Although the MPI version displayed good scalability, the performance was diminished for large numbers of MPI processes due to the overhead associated with MPI communications between nodes. This issue was partially overcome by the hybrid MPI/OpenMP approach which displayed a better scalability for a larger number of CPU cores (up to 64 CPUs in the tested systems).

  • 19. Ovchinnikov, Victor
    et al.
    Nam, Kwangho
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Karplus, Martin
    A Simple and Accurate Method To Calculate Free Energy Profiles and Reaction Rates from Restrained Molecular Simulations of Diffusive Processes2016Ingår i: Journal of Physical Chemistry B, ISSN 1520-6106, E-ISSN 1520-5207, Vol. 120, nr 33, s. 8457-8472Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    A method is developed to obtain simultaneously free energy profiles and diffusion constants from restrained molecular simulations in diffusive systems. The method is based on low-order expansions of the free energy and diffusivity as functions of the reaction coordinate. These expansions lead to simple analytical relationships between simulation statistics and model parameters. The method is tested on 1D and 2D model systems; its accuracy is found to be comparable to or better than that of the existing alternatives, which are briefly discussed. An important aspect of the method is that the free energy is constructed by integrating its derivatives, which can be computed without need for overlapping sampling windows. The implementation of the method in any molecular simulation program that supports external umbrella potentials (e.g., CHARMM) requires modification of only a few lines of code. As a demonstration of its applicability to realistic biomolecular systems, the method is applied to model the alpha-helix <-> beta-sheet transition in a 16-residue peptide in implicit solvent, with the reaction coordinate provided by the string method. Possible modifications of the method are briefly discussed; they include generalization to multidimensional reaction coordinates [in the spirit of the model of Ermak and McCammon (Ermak, D. L.; McCammon, J. A. J. Chem. Phys. 1978, 69, 1352-1360)], a higher-order expansion of the free energy surface, applicability in nonequilibrium systems, and a simple test for Markovianity. In view of the small overhead of the method relative to standard umbrella sampling, we suggest its routine application in the cases where umbrella potential simulations are appropriate.

  • 20. Spulber, S.
    et al.
    Raciti, M.
    Dulko-Smith, B.
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen. University of Texas at Arlington, Department of Chemistry and Biochemistry, Arlington, TX, USA.
    Lupu, D.
    Ruegg, J.
    Nam, Kwangho
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen. University of Texas at Arlington, Department of Chemistry and Biochemistry, Arlington, TX, USA.
    Ceccatelli, S.
    Methylmercury interferes with glucocorticoid receptor: Potential role in the mediation of developmental neurotoxicity2018Ingår i: Toxicology and Applied Pharmacology, ISSN 0041-008X, E-ISSN 1096-0333, Vol. 354, s. 94-100Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Methylmercury (MeHg) is a widespread environmental contaminant with established developmental neurotoxic effects. Computational models have identified glucocorticoid receptor (GR) signaling to be a key mediator behind the birth defects induced by Hg, but the mechanisms were not elucidated. Using molecular dynamics simulations, we found that MeHg can bind to the GR protein at Cys736 (located close to the ligand binding site) and distort the conformation of the ligand binging site. To assess the functional consequences of MeHg interaction with GR, we used a human cell line expressing a luciferase reporter system (HeLa AZ-GR). We found that 100 nM MeHg does not have any significant effect on GR activity alone, but the transactivation of gene expression by GR upon Dex (a synthetic GR agonist) administration was reduced in cells pre-treated with MeHg. Similar effects were found in transgenic zebrafish larvae expressing a GR reporter system (SR4G). Next we asked whether the effects of developmental exposure to MeHg are mediated by the effects on GR. Using a mutant zebrafish line carrying a loss-of-function mutation in the GR (grs(357)) we could show that the effects of developmental exposure to 2.5 nM MeHg are mitigated in absence of functional GR signaling. Taken together, our data indicate that inhibition of GR signaling may have a role in the developmental neurotoxic effects of MeHg.

  • 21. Yeh, Johannes T. -H.
    et al.
    Nam, Kwangho
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen. Department of Chemistry and Biochemistry, University of Texas at Arlington, Arlington, TX, 76019-0065, USA.
    Yeh, Joshua T. -H.
    Perrimon, Norbert
    eUnaG: a new ligand-inducible fluorescent reporter to detect drug transporter activity in live cells2017Ingår i: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 7, artikel-id 41619Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The absorption, distribution, metabolism and excretion (ADME) of metabolites and toxic organic solutes are orchestrated by the ATP-binding cassette (ABC) transporters and the organic solute carrier family (SLC) proteins. A large number of ABC and SLC transpoters exist; however, only a small number have been well characterized. To facilitate the analysis of these transporters, which is important for drug safety and physiological studies, we developed a sensitive genetically encoded bilirubin (BR)-inducible fluorescence sensor (eUnaG) to detect transporter-coupled influx/efflux of organic compounds. This sensor can be used in live cells to measure transporter activity, as excretion of BR depends on ABC and SLC transporters. Applying eUnaG in functional RNAi screens, we characterize l(2) 03659 as a Drosophila multidrug resistant-associated ABC transporter.

  • 22.
    Zhang, Jin
    et al.
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Li, Yaozong
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Gupta, Arun A.
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Nam, Kwangho
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Andersson, Patrik L.
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Identification and Molecular Interaction Studies of Thyroid Hormone Receptor Disruptors among Household Dust Contaminants2016Ingår i: Chemical Research in Toxicology, ISSN 0893-228X, E-ISSN 1520-5010, Vol. 29, nr 8, s. 1345-1354Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Thyroid hormone disrupting chemicals (THDCs), often found abundantly in the environment, interfere with normal thyroid hormone signaling and induce physiological malfunctions, possibly by affecting thyroid hormone receptors (THRs). Indoor dust ingestion is a significant human exposure route of THDCs, raising serious concerns for human health. Here, we developed a virtual screening protocol based on an ensemble of X-ray crystallographic structures of human THRβ1 and the generalized Born solvation model to identify potential THDCs targeting the human THRβ1 isoform. The protocol was applied to virtually screen an in-house indoor dust contaminant inventory, yielding 31 dust contaminants as potential THRβ1 binders. Five predicted binders and one negative control were tested using isothermal titration calorimetry, of which four, i.e., 2,4,5-trichlorophenoxyacetic acid (2,4,5-T), bisphenol A (3-chloro-2-hydroxypropyl) (2,3-dihydroxypropyl) ether (BADGE-HCl-H2O), 2,2',4,4'-tetrahydroxybenzophenone (BP2), and 2,4-dichlorophenoxyacetic acid (2,4-D), were identified as THRβ1 binders with binding affinities ranging between 60 μM and 460 μM. Molecular dynamics (MD) simulations were employed to examine potential binding modes of these binders and provided a rationale for explaining their specific recognition by THRβ1. The combination of in vitro binding affinity measurements and MD simulations allowed identification of four new potential THR-targeting THDCs that have been found in household dust. We suggest using the developed structure-based virtual screening protocol to identify and prioritize testing of potential THDCs.

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