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Nam, Kwangho
Publications (10 of 23) Show all publications
Asgari, P., Hua, Y., Bokka, A., Thiamsiri, C., Prasitwatcharakorn, W., Karedath, A., . . . Jeon, J. (2019). Catalytic hydrogen atom transfer from hydrosilanes to vinylarenes for hydrosilylation and polymerization. Nature Catalysis, 2(2), 164-173
Open this publication in new window or tab >>Catalytic hydrogen atom transfer from hydrosilanes to vinylarenes for hydrosilylation and polymerization
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2019 (English)In: Nature Catalysis, ISSN 2520-1158, Vol. 2, no 2, p. 164-173Article in journal (Refereed) Published
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.

Place, publisher, year, edition, pages
Nature Publishing Group, 2019
National Category
Organic Chemistry
Identifiers
urn:nbn:se:umu:diva-156880 (URN)10.1038/s41929-018-0217-z (DOI)000458554800012 ()
Available from: 2019-03-11 Created: 2019-03-11 Last updated: 2019-03-11Bibliographically approved
Nam, K. & Karplus, M. (2019). Insights into the origin of the high energy-conversion efficiency of F-1-ATPase. Proceedings of the National Academy of Sciences of the United States of America, 116(32), 15924-15929
Open this publication in new window or tab >>Insights into the origin of the high energy-conversion efficiency of F-1-ATPase
2019 (English)In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 116, no 32, p. 15924-15929Article in journal (Refereed) Published
Abstract [en]

Our understanding of the rotary-coupling mechanism of F-1-ATPase has been greatly enhanced in the last decade by advances in X-ray crystallography, single-molecular imaging, and theoretical models. Recently, Volkan-Kacso and Marcus [S. Volkan-Kacso, R. A. Marcus, Proc. Natl. Acad. Sci. U.S.A. 112, 14230 (2015)] presented an insightful thermodynamic model based on the Marcus reaction theory coupled with an elastic structural deformation term to explain the observed gamma-rotation angle dependence of the adenosine triphosphate (ATP)/ adenosine diphosphate (ADP) exchange rates of F-1-ATPase. Although the model is successful in correlating single-molecule data, it is not in agreement with the available theoretical results. We describe a revision of the model, which leads to consistency with the simulation results and other experimental data on the F-1-ATPase rotor compliance. Although the free energy liberated on ATP hydrolysis by F-1-ATPase is rapidly dissipated as heat and so cannot contribute directly to the rotation, we show how, nevertheless, F-1-ATPase functions near the maximum possible efficiency. This surprising result is a consequence of the differential binding of ATP and its hydrolysis products ADP and P-i along a well-defined pathway.

Place, publisher, year, edition, pages
NATL ACAD SCIENCES, 2019
Keywords
F-1-ATPase, chemo-mechanical coupling, energy-conversion efficiency, free-energy profile
National Category
Theoretical Chemistry
Identifiers
urn:nbn:se:umu:diva-162303 (URN)10.1073/pnas.1906816116 (DOI)000478971900032 ()31341091 (PubMedID)
Available from: 2019-09-10 Created: 2019-09-10 Last updated: 2019-09-10Bibliographically approved
Spulber, S., Raciti, M., Dulko-Smith, B., Lupu, D., Ruegg, J., Nam, K. & Ceccatelli, S. (2018). Methylmercury interferes with glucocorticoid receptor: Potential role in the mediation of developmental neurotoxicity. Toxicology and Applied Pharmacology, 354, 94-100
Open this publication in new window or tab >>Methylmercury interferes with glucocorticoid receptor: Potential role in the mediation of developmental neurotoxicity
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2018 (English)In: Toxicology and Applied Pharmacology, ISSN 0041-008X, E-ISSN 1096-0333, Vol. 354, p. 94-100Article in journal (Refereed) Published
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.

Place, publisher, year, edition, pages
Academic Press, 2018
Keywords
Developmental neurotoxicity, Methylmercury, Glucocorticoid receptor, Endocrine disruptor, alternative methods
National Category
Pharmacology and Toxicology Developmental Biology
Identifiers
urn:nbn:se:umu:diva-151549 (URN)10.1016/j.taap.2018.02.021 (DOI)000442335500010 ()29499248 (PubMedID)
Funder
Swedish Research Council, 2015-04114Swedish Research Council, 10815-20-4
Note

Special Issue: Alternative Approaches to Developmental Neurotoxicity Evaluation

Available from: 2018-09-11 Created: 2018-09-11 Last updated: 2018-09-11Bibliographically approved
Das, S., Nam, K. & Major, D. T. (2018). Rapid Convergence of Energy and Free Energy Profiles with Quantum Mechanical Size in Quantum Mechanical–Molecular Mechanical Simulations of Proton Transfer in DNA. Journal of Chemical Theory and Computation, 14(3), 1695-1705
Open this publication in new window or tab >>Rapid Convergence of Energy and Free Energy Profiles with Quantum Mechanical Size in Quantum Mechanical–Molecular Mechanical Simulations of Proton Transfer in DNA
2018 (English)In: Journal of Chemical Theory and Computation, ISSN 1549-9618, E-ISSN 1549-9626, Vol. 14, no 3, p. 1695-1705Article in journal (Refereed) Published
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.

Place, publisher, year, edition, pages
American Chemical Society (ACS), 2018
National Category
Theoretical Chemistry
Identifiers
urn:nbn:se:umu:diva-146449 (URN)10.1021/acs.jctc.7b00964 (DOI)000427661400047 ()29446946 (PubMedID)
Available from: 2018-05-03 Created: 2018-05-03 Last updated: 2018-06-09Bibliographically approved
Nestor, S. T., Hawkins, A. N., Xhani, X., Sykora, R. E., Mao, J. X., Nam, K., . . . Mirjafari, A. (2018). Studies on solubility and S-alkylation of 2-thiouracil in ionic liquids. Journal of Molecular Liquids, 265, 463-467
Open this publication in new window or tab >>Studies on solubility and S-alkylation of 2-thiouracil in ionic liquids
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2018 (English)In: Journal of Molecular Liquids, ISSN 0167-7322, E-ISSN 1873-3166, Vol. 265, p. 463-467Article in journal (Refereed) Published
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]. 

Place, publisher, year, edition, pages
Elsevier, 2018
Keywords
Ionic liquids, 2-Thiouracil, APIs dissolution, Drug delivery
National Category
Biochemistry and Molecular Biology
Identifiers
urn:nbn:se:umu:diva-152214 (URN)10.1016/j.molliq.2018.06.026 (DOI)000441854700050 ()
Available from: 2018-11-06 Created: 2018-11-06 Last updated: 2018-11-06Bibliographically approved
Ojeda-May, P. & Nam, K. (2017). Acceleration of Semiempirical QM/MM Methods through Message Passage Interface (MPI), Hybrid MPI/Open Multiprocessing, and Self-Consistent Field Accelerator Implementations. Journal of Chemical Theory and Computation, 13(8), 3525-3536
Open this publication in new window or tab >>Acceleration of Semiempirical QM/MM Methods through Message Passage Interface (MPI), Hybrid MPI/Open Multiprocessing, and Self-Consistent Field Accelerator Implementations
2017 (English)In: Journal of Chemical Theory and Computation, ISSN 1549-9618, E-ISSN 1549-9626, Vol. 13, no 8, p. 3525-3536Article in journal (Refereed) Published
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).

National Category
Computer Engineering
Identifiers
urn:nbn:se:umu:diva-139006 (URN)10.1021/acs.jctc.7b00322 (DOI)000407522100009 ()
Available from: 2017-09-14 Created: 2017-09-14 Last updated: 2018-06-09Bibliographically approved
Mishra, Y., Hall, M., Locmelis, R., Nam, K., Söderberg, C. A. G., Storm, P., . . . Sauer, U. H. (2017). Active-site plasticity revealed in the asymmetric dimer of AnPrx6 the 1-Cys peroxiredoxin and molecular chaperone from Anabaena sp. PCC 7120. Scientific Reports, 7, Article ID 17151.
Open this publication in new window or tab >>Active-site plasticity revealed in the asymmetric dimer of AnPrx6 the 1-Cys peroxiredoxin and molecular chaperone from Anabaena sp. PCC 7120
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2017 (English)In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 7, article id 17151Article in journal (Refereed) Published
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.

Place, publisher, year, edition, pages
Nature Publishing Group, 2017
National Category
Structural Biology
Identifiers
urn:nbn:se:umu:diva-143523 (URN)10.1038/s41598-017-17044-3 (DOI)000417354200004 ()29215017 (PubMedID)2-s2.0-85038074530 (Scopus ID)
Note

The original version of this Article contained an error in the title of the paper, where “Anabaena sp. PCC 7120” was incorrectly given as “Anabaena sp. PCC 7210”. This has now been corrected in the PDF and HTML versions of the Article, and in the accompanying Supplementary Information file.

Errata: Author Correction: Active-site plasticity revealed in the asymmetric dimer of AnPrx6 the 1-Cys peroxiredoxin and molecular chaperone from Anabaena sp. PCC 7120. Scientifc reports. 2018;8:8658. DOI: 10.1038/s41598-018-26715-8

Available from: 2018-01-04 Created: 2018-01-04 Last updated: 2018-06-15Bibliographically approved
Li, Y. & Nam, K. (2017). Dynamic, structural and thermodynamic basis of insulin-like growth factor 1 kinase allostery mediated by activation loop phosphorylation. Chemical Science, 8(5), 3453-3464
Open this publication in new window or tab >>Dynamic, structural and thermodynamic basis of insulin-like growth factor 1 kinase allostery mediated by activation loop phosphorylation
2017 (English)In: Chemical Science, ISSN 2041-6539, Vol. 8, no 5, p. 3453-3464Article in journal (Refereed) Published
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.

National Category
Theoretical Chemistry
Research subject
Cancer Epidemiology
Identifiers
urn:nbn:se:umu:diva-134864 (URN)10.1039/c7sc00055c (DOI)000400553000017 ()28507717 (PubMedID)
Available from: 2017-05-14 Created: 2017-05-14 Last updated: 2018-06-09Bibliographically approved
Yeh, J.-H. T. -., Nam, K., Yeh, J.-H. T. -. & Perrimon, N. (2017). eUnaG: a new ligand-inducible fluorescent reporter to detect drug transporter activity in live cells. Scientific Reports, 7, Article ID 41619.
Open this publication in new window or tab >>eUnaG: a new ligand-inducible fluorescent reporter to detect drug transporter activity in live cells
2017 (English)In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 7, article id 41619Article in journal (Refereed) Published
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.

Place, publisher, year, edition, pages
Nature Publishing Group, 2017
National Category
Biochemistry and Molecular Biology
Identifiers
urn:nbn:se:umu:diva-132128 (URN)10.1038/srep41619 (DOI)000393605700001 ()28176814 (PubMedID)
Available from: 2017-03-09 Created: 2017-03-09 Last updated: 2018-06-09Bibliographically approved
Nam, K. (2017). New repulsive soft-core potential for accelerated alchemical free energy calculations. Paper presented at 254th National Meeting and Exposition of the American-Chemical-Society (ACS) on Chemistry's Impact on the Global Economy, AUG 20-24, 2017, Washington, DC. Abstract of Papers of the American Chemical Society, 254
Open this publication in new window or tab >>New repulsive soft-core potential for accelerated alchemical free energy calculations
2017 (English)In: Abstract of Papers of the American Chemical Society, ISSN 0065-7727, Vol. 254Article in journal, Meeting abstract (Other academic) Published
Place, publisher, year, edition, pages
American Chemical Society (ACS), 2017
National Category
Chemical Sciences
Identifiers
urn:nbn:se:umu:diva-147226 (URN)000429525603656 ()
Conference
254th National Meeting and Exposition of the American-Chemical-Society (ACS) on Chemistry's Impact on the Global Economy, AUG 20-24, 2017, Washington, DC
Note

Meeting Abstract: 112

Available from: 2018-05-02 Created: 2018-05-02 Last updated: 2018-06-09Bibliographically approved
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