| 1. |
- Asgari, Parham, et al.
(författare)
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Catalytic hydrogen atom transfer from hydrosilanes to vinylarenes for hydrosilylation and polymerization
- 2019
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Ingår i: Nature Catalysis. - : Nature Publishing Group. - 2520-1158. ; 2:2, s. 164-173
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Tidskriftsartikel (refereegranskat)abstract
- 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.
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| 2. |
- Das, Susanta, et al.
(författare)
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Rapid Convergence of Energy and Free Energy Profiles with Quantum Mechanical Size in Quantum Mechanical–Molecular Mechanical Simulations of Proton Transfer in DNA
- 2018
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Ingår i: Journal of Chemical Theory and Computation. - : American Chemical Society (ACS). - 1549-9618 .- 1549-9626. ; 14:3, s. 1695-1705
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Tidskriftsartikel (refereegranskat)abstract
- 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.
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| 3. |
- Doron, Dvir, et al.
(författare)
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How Accurate Are Transition States from Simulations of Enzymatic Reactions?
- 2014
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Ingår i: Journal of Chemical Theory and Computation. - : American Chemical Society (ACS). - 1549-9618 .- 1549-9626. ; 10:5, s. 1863-1871
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Tidskriftsartikel (refereegranskat)abstract
- 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.
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| 4. |
- Dulko-Smith, Beata, et al.
(författare)
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Mechanistic basis for a connection between the catalytic step and slow opening dynamics of adenylate kinase
- 2023
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Ingår i: Journal of Chemical Information and Modeling. - : American Chemical Society (ACS). - 1549-9596 .- 1549-960X. ; 63:5, s. 1556-1569
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Tidskriftsartikel (refereegranskat)abstract
- Escherichia coli adenylate kinase (AdK) is a small, monomeric enzyme that synchronizes the catalytic step with the enzyme’s conformational dynamics to optimize a phosphoryl transfer reaction and the subsequent release of the product. Guided by experimental measurements of low catalytic activity in seven single-point mutation AdK variants (K13Q, R36A, R88A, R123A, R156K, R167A, and D158A), we utilized classical mechanical simulations to probe mutant dynamics linked to product release, and quantum mechanical and molecular mechanical calculations to compute a free energy barrier for the catalytic event. The goal was to establish a mechanistic connection between the two activities. Our calculations of the free energy barriers in AdK variants were in line with those from experiments, and conformational dynamics consistently demonstrated an enhanced tendency toward enzyme opening. This indicates that the catalytic residues in the wild-type AdK serve a dual role in this enzyme’s function─one to lower the energy barrier for the phosphoryl transfer reaction and another to delay enzyme opening, maintaining it in a catalytically active, closed conformation for long enough to enable the subsequent chemical step. Our study also discovers that while each catalytic residue individually contributes to facilitating the catalysis, R36, R123, R156, R167, and D158 are organized in a tightly coordinated interaction network and collectively modulate AdK’s conformational transitions. Unlike the existing notion of product release being rate-limiting, our results suggest a mechanistic interconnection between the chemical step and the enzyme’s conformational dynamics acting as the bottleneck of the catalytic process. Our results also suggest that the enzyme’s active site has evolved to optimize the chemical reaction step while slowing down the overall opening dynamics of the enzyme.
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| 5. |
- Huang, Yang, 1985-, et al.
(författare)
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The water R1(ω) NMRD profiles of a hydrated protein from molecular dynamics simulation
- 2013
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Ingår i: Physical Chemistry, Chemical Physics - PCCP. - : RSC Publishing. - 1463-9076 .- 1463-9084. ; 15:33, s. 14089-14097
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Tidskriftsartikel (refereegranskat)abstract
- 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(ω 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.
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| 6. |
- Koag, Myong-Chul, et al.
(författare)
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The spontaneous replication error and the mismatch discrimination mechanisms of human DNA polymerase beta
- 2014
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Ingår i: Nucleic Acids Research. - : Oxford University Press (OUP). - 0305-1048 .- 1362-4962. ; 42:17, s. 11233-11245
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Tidskriftsartikel (refereegranskat)abstract
- 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.
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| 7. |
- Li, Yaozong, et al.
(författare)
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Dynamic, structural and thermodynamic basis of insulin-like growth factor 1 kinase allostery mediated by activation loop phosphorylation
- 2017
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Ingår i: Chemical Science. - : Royal Society of Chemistry (RSC). - 2041-6539 .- 2041-6520. ; 8:5, s. 3453-3464
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Tidskriftsartikel (refereegranskat)abstract
- 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.
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| 8. |
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| 9. |
- Li, Yaozong, et al.
(författare)
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Repulsive Soft-Core Potentials for Efficient Alchemical Free Energy Calculations
- 2020
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Ingår i: Journal of Chemical Theory and Computation. - : American Chemical Society (ACS). - 1549-9618 .- 1549-9626. ; 16:8, s. 4776-4789
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Tidskriftsartikel (refereegranskat)abstract
- In alchemical free energy (FE) simulations, annihilation and creation of atoms are generally achieved with the soft-core potential that shifts the interparticle separations. While this soft-core potential eliminates the numerical instability occurring near the two end states of the transformation, it makes the hybrid Hamiltonian vary nonlinearly with respect to the parameter λ, which interpolates between the Hamiltonians representing the two end states. This complicates FE estimation by Bennett acceptance ratio (BAR), free energy perturbation (FEP), and thermodynamic integration (TI) methods, thus reducing their calculation efficiency. In this work, we develop a new type of repulsive soft-core potential, called Gaussian soft-core (GSC) potential, with two parameters controlling its maximum and width. The main advantage of this potential is the linearity of the hybrid Hamiltonian with respect to λ, thus permitting the direct application of BAR, FEP, TI, and other variant FE methods. The accuracy and efficiency of the GSC potential are demonstrated by comparing the free energies of annihilation determined for 13 small molecules and an alchemical mutation of a protein side chain. In addition, in combination with a TI integrand (∂H/∂λ) estimation strategy, we show that GSC can considerably reduce the number of λ simulations compared to the commonly used separation-shifted soft-core potential.
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| 10. |
- Li, Yaozong, 1982-
(författare)
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Understanding molecular mechanisms of protein tyrosine kinases by molecular dynamics and free energy calculations
- 2017
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Background: Insulin receptor kinase (IRK) and Insulin-like growth factor 1 receptor kinase (IGF-1RK) are two important members in the large class of tyrosine kinase receptors. They play pivotalroles in the regulation of glucose homeostasis, cell proliferation, differentiation, motility, andtransformation. Their dysfunctions are linked to diabetes, rheumatoid arthritis and many cancers.Although their regulatory mechanisms have been widely studied experimentally, the atomisticdetails are still poorly understood, especially for the influences caused by activation loop (A-loop)phosphorylation.Methods: Molecular dynamics (MD) and alchemical free energy simulations are carried out tounderstand mechanisms underlying the kinase proteins regulation and their thermodynamic basis.To capture a full picture about the entire kinase catalytic cycle, different functional steps areconsidered, i.e., conformational transition, substrate binding, phosphoryl transfer and productrelease. The effects of the A-loop phosphorylation on protein’s dynamics, structure, stability, andfree energy landscape are examined by various analysis methods, including principle componentanalysis (PCA), motion projection, dynamical network analysis and free energy perturbation.Results: The main findings are: 1) A-loop phosphorylation shifts the kinase conformationalpopulation to the active one by changing the electrostatic environments in the kinase apo form, 2)allosterically fine-tunes the orientation of the catalytic residues mediated by the >C-helix in thereactant and product binding states, and 3) thermodynamically favors the kinase catalysis presentedby a catalytic-cycle-mimic free energy landscape. An integrated view on the roles of A-loopphosphorylation in kinase allostery is developed by incorporating kinase’s dynamics, structuralinteractions, thermodynamics and free energy landscape. In addition, new soft-core potentials(Gaussian soft-core) and protocols are developed to conduct accurate and efficient alchemical freeenergy calculations.Conclusions: The entire catalytic cycle is examined by MD and free energy calculations andcomprehensive analyses are conducted. The findings from the studied kinases are general and canbe implemented to the other members in IRK family or even to more non-homologous familiesbecause of the conservation of the characteristic residues between their A-loop and >C-helix. Inaddition, the Gaussian soft-core potentials provide a new tool to perform alchemical free energycalculations in an efficient way.
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