| 1. |
- Al-Smadi, Derar, 1983-, et al.
(författare)
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Chemical and Biochemical Approaches for the Synthesis of Substituted Dihydroxybutanones and Di-, and Tri-Hydroxypentanones
- 2019
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Ingår i: Journal of Organic Chemistry. - : American Chemical Society (ACS). - 0022-3263 .- 1520-6904. ; 84:11, s. 6982-6991
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Tidskriftsartikel (refereegranskat)abstract
- Polyhydroxylated compounds are building blocks for the synthesis of carbohydrates and other natural products. Their synthesis is mainly achieved by different synthetic versions of aldol-coupling reactions, catalyzed either by organocatalysts, enzymes or metal-organic catalysts. We have investigated the formation of 1,4-substituted 2,3-dihydroxybutan-1-one derivatives from para- and meta-substituted phenylacetaldehydes by three distinctly different strategies. The first involved a direct aldol reaction with hydroxyacetone, dihydroxyacetone or 2-hydroxyacetophenone, catalyzed by the cinchona derivative cinchonine. The second was reductive cross-coupling with methyl or phenyl glyoxal promoted by SmI2 resulting in either 5-substituted 3,4-dihydroxypentan-2-ones or 1,4 bis-phenyl substituted butanones, respectively. Finally, in the third case, aldolase catalysis was employed for synthesis of the corresponding 1,3,4-trihydroxylated pentan-2-one derivatives. The organocatalytic route with cinchonine generated distereomerically enriched syn products (de = 60−99 %), with moderate enantiomeric excesses (ee = 43−56%), but did not produce aldols with either hydroxyacetone or dihydroxyacetone as donor ketones. The SmI2-promoted reductive cross-coupling generated product mixtures with diastereomeric and enantiomeric ratios close to unity. This route allowed for the production of both 1-methyl- and 1-phenylsubstituted 2,3-dihydroxybutanones, at yields between 40−60%. Finally, the biocatalytic approach resulted in enantiopure syn (3R,4S) 1,3,4-trihydroxypentan-2-ones.
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| 2. |
- Calixto, Ana Rita, et al.
(författare)
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Recent Advances in Understanding Biological GTP Hydrolysis through Molecular Simulation
- 2020
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Ingår i: ACS Omega. - : American Chemical Society (ACS). - 2470-1343. ; 5:9, s. 4380-4385
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Forskningsöversikt (refereegranskat)abstract
- GTP hydrolysis is central to biology, being involved in regulating a wide range of cellular processes. However, the mechanisms by which GTPases hydrolyze this critical reaction remain controversial, with multiple mechanistic possibilities having been proposed based on analysis of experimental and computational data. In this mini-review, we discuss advances in our understanding of biological GTP hydrolysis based on recent computational studies and argue in favor of solvent-assisted hydrolysis as a conserved mechanism among GTPases. A concrete understanding of the fundamental mechanisms by which these enzymes facilitate GTP hydrolysis will have significant impact both for drug discovery efforts and for unraveling the role of oncogenic mutations.
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| 3. |
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| 4. |
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| 5. |
- Kamerlin, Shina Caroline Lynn, 1981-, et al.
(författare)
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Female Faculty: Why So Few and Why Care?
- 2020
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Ingår i: Chemistry - A European Journal. - : Wiley. - 1521-3765 .- 0947-6539. ; 26:38, s. 8319-8323
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)abstract
- Despite slow ongoing progress in increasing the representation of women in academia, women remain significantly under-represented at senior levels, in particular in the natural sciences and engineering. Not infrequently, this is downplayed by bringing forth arguments such as inherent biological differences between genders, that current policies are adequate to address the issue, or by deflecting this as being “not my problem” among other examples. In this piece we present scientific evidence that counters these claims, as well as a best-practice example, Genie, from Chalmers University of Technology, where one of the authors is currently employed. We also highlight particular challenges caused by the current COVID-19 pandemic. Finally, we conclude by proposing some possible solutions to the situation and emphasize that we need to all do our part, to ensure that the next generation of academics experience a more diverse, inclusive, and equitable working environment.
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| 6. |
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| 7. |
- Kamerlin, Shina Caroline Lynn, 1981-
(författare)
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Open Access, Plan S, and researchers' needs
- 2020
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Ingår i: EMBO Reports. - : EMBO. - 1469-221X .- 1469-3178. ; 21:10
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)abstract
- Mandates with the aim to enforce Open Access publishing, such as Plan S, need to respect researchers' needs and should contribute to the broader goal of Open Science.
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| 8. |
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| 10. |
- Kamerlin, Shina Caroline Lynn, 1981-
(författare)
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Theoretical comparison of p-nitrophenyl phosphate and sulfate Hydrolysis in aqueous solution: implications for enzyme-catalyzed sulfuryl transfer
- 2011
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Ingår i: Journal of Organic Chemistry. - : American Chemical Society. - 0022-3263 .- 1520-6904. ; 76:22, s. 9228-9238
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Tidskriftsartikel (refereegranskat)abstract
- Both phosphoryl and sulfuryl transfers are ubiquitous in biology, being involved in a wide range of processes, ranging from cell division to apoptosis. Additionally, it is becoming increasingly clear that enzymes that can catalyze phosphoryl transfer can often cross-catalyze sulfuryl transfer (and vice versa). However, while there have been extensive experimental and theoretical studies performed on phosphoryl transfer, the body of available research on sulfuryl transfer is comparatively much smaller. The present work presents a direct theoretical comparison of p-nitrophenyl phosphate and sulfate monoester hydrolysis, both of which are considered prototype systems for probing phosphoryl and sulfuryl transfer, respectively. Specifically, free energy surfaces have been generated using density functional theory, by initial geometry optimization in PCM using the 6-31+G* basis set and the B3LYP density functional, followed by single-point calculations using the larger 6-311+G** basis set and the COSMO continuum model. The resulting surfaces have been then used to identify the relevant transition states, either by further unconstrained geometry optimization or from the surface itself where possible. Additionally, configurational entropies were evaluated using a combination of the quasiharmonic approximation and the restraint release approach and added to the calculated activation barriers as a correction. Finally, the overall activation entropy was estimated by approximating the solvent contribution to the total activation entropy using the Langevin dipoles solvation model. We have reproduced both the experimentally observed activation barriers and the observed trend in the activation entropies with reasonable accuracy, as well as providing a comparison of calculated and observed 15N and 18O kinetic isotope effects. We demonstrate that, counterintuitively, the hydrolysis of the p-nitrophenyl sulfate proceeds through a more expansive pathway than its phosphate analogue. Additionally, we show that the solvation effects upon moving from the ground state to the transition state are quite different for both reactions, suggesting that the enzymes that catalyze these reactions would need active sites with quite different electrostatic preorganization for the efficient catalysis of either reaction (despite which many enzymes can catalyze both phosphoryl and sulfuryl transfer). We believe that such a comparative study is an important foundation for understanding the molecular basis for phosphate–sulfate cross-promiscuity within members of the alkaline phosphatase superfamily.
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| 11. |
- Kamerlin, Shina Caroline Lynn, 1981-
(författare)
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Where are the female science professors? A personal perspective
- 2016
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Ingår i: F1000 Research. - : F1000 Research Ltd. - 2046-1402. ; 5
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Tidskriftsartikel (refereegranskat)abstract
- The first woman to earn a Professorship at a University in Europe was Laura Maria Caterina Bassi, who earned a professorship in physics at the University of Bologna in 1732. Almost 300 years and three waves of feminism later, in 2016, women typically still only comprise 20% (or less) of the number of full professors in Europe. This opinion article will discuss the experiences of being a female academic today and the factors contributing to the academic gender gap from the perspective of a “young” natural scientist, as well as providing constructive suggestions for strategies to empower women in the academic world.
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| 12. |
- Liao, Qinghua, et al.
(författare)
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Extending the Nonbonded Cationic Dummy Model to Account for Ion-Induced Dipole Interactions
- 2017
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Ingår i: The Journal of Physical Chemistry Letters. - : American Chemical Society (ACS). - 1948-7185. ; 8:21, s. 5408-5414
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Tidskriftsartikel (refereegranskat)abstract
- Modeling metalloproteins often requires classical molecular dynamics (MD) simulations in order to capture their relevant motions, which in turn necessitates reliable descriptions of the metal centers involved. One of the most successful approaches to date is provided by the "cationic dummy model", where the positive charge of the metal ion is transferred toward dummy particles that are bonded to the central metal ion in a predefined coordination geometry. While this approach allows for ligand exchange, and captures the correct electrostatics as demonstrated for different divalent metal ions, current dummy models neglect ion-induced dipole interactions. In the present work, we resolve this weakness by taking advantage of the recently introduced 12-6-4 type Lennard-Jones potential to include ion-induced dipole interactions. We revise our previous dummy model for Mg2+ and demonstrate that the resulting model can simultaneously reproduce the experimental solvation free energy and metal ligand distances without the need for artificial restraints or bonds. As ion-induced dipole interactions become particularly important for highly charged metal ions, we develop dummy models for the biologically relevant ions Al3+, Fe3+, and Cr3+. Finally, the effectiveness of our new models is demonstrated in MD simulations of several diverse (and highly challenging to simulate) metalloproteins.
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| 13. |
- Liao, Qinghua, et al.
(författare)
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Long Time-Scale Atomistic Simulations of the Structure and Dynamics of Transcription Factor-DNA Recognition
- 2019
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Ingår i: Journal of Physical Chemistry B. - : American Chemical Society (ACS). - 1520-6106 .- 1520-5207. ; 123:17, s. 3576-3590
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Tidskriftsartikel (refereegranskat)abstract
- Recent years have witnessed an explosion of interest in computational studies of DNA binding proteins, including both coarse grained and atomistic simulations of transcription factor-DNA recognition, to understand how these transcription factors recognize their binding sites on the DNA with such exquisite specificity. The present study performs microsecond time scale all-atom simulations of the dimeric form of the lactose repressor (Lad), both in the absence of any DNA and in the presence of both specific and nonspecific complexes, considering three different DNA sequences. We examine, specifically, the conformational differences between specific and nonspecific protein DNA interactions, as well as the behavior of the helix-turn-helix motif of Lad when interacting with the DNA. Our simulations suggest that stable Lad binding occurs primarily to bent A-form DNA, with a loss of Lad conformational entropy and optimization of correlated conformational equilibria across the protein. In addition, binding to the specific operator sequence involves a slightly larger number of stabilizing DNA protein hydrogen bonds (in comparison to nonspecific complexes), which may account for the experimentally observed specificity for this operator. In doing so, our simulations provide a detailed atomistic description of potential structural drivers for LacI selectivity.
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| 14. |
- Marsavelski, Aleksandra, et al.
(författare)
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Empirical Valence Bond Simulations Suggest a Direct Hydride Transfer Mechanism for Human Diamine Oxidase
- 2018
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Ingår i: ACS Omega. - : American Chemical Society (ACS). - 2470-1343. ; 3:4, s. 3665-3674
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Tidskriftsartikel (refereegranskat)abstract
- Diamine oxidase (DAO) is an enzyme involved in the regulation of cell proliferation and the immune response. This enzyme performs oxidative deamination in the catabolism of biogenic amines, including, among others, histamine, putrescine, spermidine, and spermine. The mechanistic details underlying the reductive half-reaction of the DAO-catalyzed oxidative deamination which leads to the reduced enzyme cofactor and the aldehyde product are, however, still under debate. The catalytic mechanism was proposed to involve a prototropic shift from the substrateSchiff base to the product-Schiff base, which includes the ratelimiting cleavage of the C alpha-H bond by the conserved catalytic aspartate. Our detailed mechanistic study, performed using a combined quantum chemical cluster approach with empirical valence bond simulations, suggests that the rate-limiting cleavage of the C alpha-H bond involves direct hydride transfer to the topaquinone cofactor. a mechanism that does not involve the formation of a Schiff base. Additional investigation of the D373E and D373N variants supported the hypothesis that the conserved catalytic aspartate is indeed essential for the reaction; however, it does not appear to serve as the catalytic base, as previously suggested. Rather, the electrostatic contributions of the most significant residues (including D373), together with the proximity of the Cu2+ cation to the reaction site, lower the activation barrier to drive the chemical reaction.
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| 15. |
- Maximoff, Sergey N., et al.
(författare)
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DNA Polymerase lambda Active Site Favors a Mutagenic Mispair between the Enol Form of Deoxyguanosine Triphosphate Substrate and the Keto Form of Thymidine Template : A Free Energy Perturbation Study
- 2017
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Ingår i: Journal of Physical Chemistry B. - : American Chemical Society (ACS). - 1520-6106 .- 1520-5207. ; 121:33, s. 7813-7822
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Tidskriftsartikel (refereegranskat)abstract
- Human DNA polymerise lambda is an intermediate fidelity member of the X family, which plays a role in DNA repair. Recent X-ray diffraction structures of a ternary complex of a loop-deletion mutant of polymerase 2, a deoxyguanosine triphosphate analogue, and a gapped DNA show that guanine and thymine form a mutagenic mispair with an . unexpected Watson Crick-like geometry rather than a wobble geometry. Hence, there is an intriguing possibility that either thyMine in the DNA or guanine in the deoxyguanosine triphosphate analogue may Spend, a substantial fraction of time in a deprotonated or enol form (both are minor species in aqueous solution) in the active site of the,polymerase lambda mutant. The experiments do not determine particular forms of the nucleobases that contribute to this mutagenic mispair. Thus, We investigate the thermodynamics of formation of various mispairs between guanine and thymine in the ternary complex at a neutral pH using classical molecular dynamics simulations and the free energy perturbation method. Our free energy calculations, as well as a comparison of the experimental and computed structures of mispairs, indicate that the Watson-Crick-like mispair between the enol tautomer of guanine and the keto tautomer of thymine is dominant. The wobble mispair between the keto forms of guanine and thymine and the Watson Crick-like mispair between the keto tautomer of guanine and the enol tautomer of thymine are less prevalent, and mispairs that involve deprotonated guanine or thymine are thermodynamically unlikely. These findings are consistent with the experiment and relevant for understanding mechanisms of spontaneous mutagenesis.
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| 16. |
- Moreira, Catia, et al.
(författare)
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The role of ligand-gated conformational changes in enzyme catalysis
- 2019
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Ingår i: Biochemical Society Transactions. - : Portland Press. - 0300-5127 .- 1470-8752. ; 47:5, s. 1449-1460
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Tidskriftsartikel (refereegranskat)abstract
- Structural and biochemical studies on diverse enzymes have highlighted the importance of ligand-gated conformational changes in enzyme catalysis, where the intrinsic binding energy of the common phosphoryl group of their substrates is used to drive energetically unfavorable conformational changes in catalytic loops, from inactive open to catalytically competent closed conformations. However, computational studies have historically been unable to capture the activating role of these conformational changes. Here, we discuss recent experimental and computational studies, which can remarkably pinpoint the role of ligand-gated conformational changes in enzyme catalysis, even when not modeling the loop dynamics explicitly. Finally, through our joint analyses of these data, we demonstrate how the synergy between theory and experiment is crucial for furthering our understanding of enzyme catalysis
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| 17. |
- Mydy, Lisa S., et al.
(författare)
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Human Glycerol 3-Phosphate Dehydrogenase : X-ray Crystal Structures That Guide the Interpretation of Mutagenesis Studies
- 2019
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Ingår i: Biochemistry. - : AMER CHEMICAL SOC. - 0006-2960 .- 1520-4995. ; 58:8, s. 1061-1073
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Tidskriftsartikel (refereegranskat)abstract
- Human liver glycerol 3-phosphate dehydrogenase (hlGPDH) catalyzes the reduction of dihydroxyacetone phosphate (DHAP) to form glycerol 3-phosphate, using the binding energy associated with the nonreacting phosphodianion of the substrate to properly orient the enzyme-substrate complex within the active site. Herein, we report the crystal structures for unliganded, binary E.NAD, and ternary E.NAD.DHAP complexes of wild type hlGPDH, illustrating a new position of DHAP, and probe the kinetics of multiple mutant enzymes with natural and truncated substrates. Mutation of Lys120, which is positioned to donate a proton to the carbonyl of DHAP, results in similar increases in the activation barrier to hlGPDH-catlyzed reduction of DHAP and to phosphite dianion-activated reduction of glycolaldehyde, illustrating that these transition states show similar interactions with the cationic K120 side chain. The K120A mutation results in a 5.3 kcal/mol transition state destabilization, and 3.0 kcal/mol of the lost transition state stabilization is rescued by 1.0 M ethylammonium cation. The 6.5 kcal/mol increase in the activation barrier observed for the D260G mutant hlGPDH-catalyzed reaction represents a 3.5 kcal/mol weakening of transition state stabilization by the K120A side chain and a 3.0 kcal/mol weakening of the interactions with other residues. The interactions, at the enzyme active site, between the K120 side chain and the Q295 and R269 side chains were likewise examined by double-mutant analyses. These results provide strong evidence that the enzyme rate acceleration is due mainly or exclusively to transition state stabilization by electrostatic interactions with polar amino acid side chains.
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| 18. |
- Petrovic, Dusan, et al.
(författare)
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Conformational dynamics and enzyme evolution
- 2018
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Ingår i: Journal of the Royal Society Interface. - : The Royal Society. - 1742-5689 .- 1742-5662. ; 15:144
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Forskningsöversikt (refereegranskat)abstract
- Enzymes are dynamic entities, and their dynamic properties are clearly linked to their biological function. It follows that dynamics ought to play an essential role in enzyme evolution. Indeed, a link between conformational diversity and the emergence of new enzyme functionalities has been recognized for many years. However, it is only recently that state-of-the-art computational and experimental approaches are revealing the crucial molecular details of this link. Specifically, evolutionary trajectories leading to functional optimization for a given host environment or to the emergence of a new function typically involve enriching catalytically competent conformations and/or the freezing out of non-competent conformations of an enzyme. In some cases, these evolutionary changes are achieved through distant mutations that shift the protein ensemble towards productive conformations. Multifunctional intermediates in evolutionary trajectories are probably multi-conformational, i.e. able to switch between different overall conformations, each competent for a given function. Conformational diversity can assist the emergence of a completely new active site through a single mutation by facilitating transition-state binding. We propose that this mechanism may have played a role in the emergence of enzymes at the primordial, progenote stage, where it was plausibly promoted by high environmental temperatures and the possibility of additional phenotypic mutations.
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