Gauging the Flexibility of the Active Site in Soybean Lipoxygenase-1 (SLO-1) through an Atom-Centered Density Matrix Propagation (ADMP) Treatment That Facilitates the Sampling of Rare Events

Phatak, Prasad; Sumner, Isaiah; Iyengar, Srinivasan S.

doi:10.1021/jp3015047

Cited by 31 publications

(54 citation statements)

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“…47 (iv, v) Similar behavior displayed in a larger model system. 47 hydrogen atom bound to the acceptor oxygen is replaced by its deuterated counterpart. To inspect secondary effects arising from the donor-side, linoleic acid scaffold, we consider a vibrational analysis which allows us to compute the vibrational coupling involved during the process of a productive (prone to hydrogen transfer) dynamics trajectory.…”

Section: Introductionmentioning

confidence: 59%

“…The precise location of the shifted transition state, however, depends on the populations of each hydrogen and deuterium eigenstate during dynamics. 45 as facilitated by the ONIOM procedure, 79,89,95,96 with an asymptotic boundary condition treatment to facilitate the study of the full enzyme, 47 and (c) includes bath variables that guide the nuclear dynamics in the direction of rare events. The approach in ref 47 is suited to treat polarization effects as encountered during processes such as hydrogen transfer reactions and was used to gauge the effect of the flexibility of the active site amino acid groups on the rate determining hydrogen transfer event in the SLO-1 catalyzed oxidation process of linoleic acid.…”

Section: Introductionmentioning

confidence: 99%

“…We thus consider four different isotopologues of the SLO-1 active site that are represented using the nomenclature CHOH, CHOD, CDOH, and CDOD where CX refers to the donor C 11 −H/D group and OX refers to the acceptor O−H/D group. We construct a large number of atom-centered density matrix propagation trajectories (ADMP) 47 that sample rare events for these systems. The rationale behind our choice to probe these secondary hydrogen bonds arises from previous studies 98 where deuterium substitutions in hydrogen bonded systems leads to large variations in the manner in which vibrational modes couple and energy gets redistributed.…”

Section: Introductionmentioning

confidence: 99%

“…At the end, by probing the microscopic role of the donor side and acceptor side groups, we are in a position to suggest experimental mutations that could gauge this effect. This paper is organized as follows: The rare events sampling methodology is summarized in Appendix A since it is already presented in detail in ref 47. To probe the isotope dependent dynamical interplay between the various active site vibrational degrees of freedom and the hydrogen transfer event, we employ the techniques discussed in section II.…”

Section: Introductionmentioning

confidence: 99%

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Active Site Dynamical Effects in the Hydrogen Transfer Rate-limiting Step in the Catalysis of Linoleic Acid by Soybean Lipoxygenase-1 (SLO-1): Primary and Secondary Isotope Contributions

et al. 2015

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Using ab initio molecular dynamics (AIMD) simulations that facilitate the treatment of rare events, we probe the active site participation in the rate-determining hydrogen transfer step in the catalytic oxidation of linoleic acid by soybean lipoxygenase-1 (SLO-1). The role of two different active site components is probed. (a) On the hydrogen atom acceptor side of the active site, the hydrogen bonding propensity between the acceptor side hydroxyl group, which is bound to the iron cofactor, and the backbone carboxyl group of isoleucine (residue number 839) is studied toward its role in promoting the hydrogen transfer event. Primary and secondary (H/D) isotope effects are also probed and a definite correlation with subtle secondary H/D isotope effects is found. With increasing average nuclear kinetic energy, the increase in transfer probability is enhanced due to the presence of the hydrogen bond between the backbone carbonyl of I839 and the acceptor oxygen. Further increase in average nuclear kinetic energy reduces the strength of this secondary hydrogen bond which leads to a deterioration in hydrogen transfer rates and finally embrances an Arrhenius-like behavior. (b) On the hydrogen atom donor side, the coupling between vibrational modes predominantly localized on the donor-side linoleic acid group and the reactive mode is probed. There appears to be a qualitative difference in the coupling between modes that belong to linoleic acid and the hydrogen transfer mode, for hydrogen and deuterium transfer. For example, the donor side secondary hydrogen atom is much more labile (by nearly a factor of 5) during deuterium transfer as compared to the case for hydrogen transfer. This appears to indicate a greater coupling between the modes belonging to the linoleic acid scaffold and the deuterium transfer mode and also provides a new rationalization for the abnormal (nonclassical) secondary isotope effect results obtained by Knapp, Rickert, and Klinman in J. Am. Chem. Soc. , 2002 , 124 , 3865 . To substantiate our findings noted in point a above, we have suggested an I839 → A839 or I839 → V839 mutation. This will modify the bulkiness of hydrogen the bonding residue, allowing greater flexibility in the secondary hydrogen bond formation highlighted above and adversely affecting the reaction rate.

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Section: Introductionmentioning

confidence: 59%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Active Site Dynamical Effects in the Hydrogen Transfer Rate-limiting Step in the Catalysis of Linoleic Acid by Soybean Lipoxygenase-1 (SLO-1): Primary and Secondary Isotope Contributions

et al. 2015

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“…Physical constraints on the dynamics lead to decrease in the electrostatic fluctuations, which could in turn affect the catalytic reaction. [59] …”

Section: Exploring Reaction Pathwaysmentioning

confidence: 99%

Protein effects in non-heme iron enzyme catalysis: insights from multiscale models

Vedin

Lundberg

2016

J Biol Inorg Chem

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PostprintThis is the accepted version of a paper published in Journal of Biological Inorganic Chemistry. This paper has been peer-reviewed but does not include the final publisher proof-corrections or journal pagination. Citation for the original published paper (version of record):Vedin, N P., Lundberg, M. (2016) Protein effects in non-heme iron enzyme catalysis: insights from multiscale models. from second-sphere residues. The long-range electrostatic effects on reaction barriers are small for many systems. In the systems where large electrostatic effects have been reported, these lead to higher barriers. There is thus no evidence of any significant long-range electrostatic effects contributing to the catalytic efficiency of non-heme iron enzymes. However, the correct evaluation of electrostatic contributions is challenging, and the correlation between calculated residue contributions and the effects of mutation experiments is not very strong. The largest benefits of QM/MM models are thus the improved active-site geometries, rather than the calculation of accurate energies. Reported differences in mechanistic predictions between QM and QM/MM models can be explained by differences in hydrogen bonding patterns in and around the active site. Correctly constructed cluster models can give results with similar accuracy as those from multiscale models, but the latter reduces the risk of drawing the wrong mechanistic conclusions based on incorrect geometries and are preferable for all types of modeling, even when using very large QM parts. Journal of Biological Inorganic

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Quantifying the Long‐Range Coupling of Electronic Properties in Proteins with ab initio Molecular Dynamics**

et al. 2021

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The delicate interplay of covalent and non-covalent interactions in proteins is inherently quantum mechanical and highly dynamic in nature. To directly interrogate the evolving nature of the electronic structure of proteins, we carry out 100-ps-scale ab initio molecular dynamics simulations of three representative small proteins with range-separated hybrid density functional theory. We quantify the nature and length-scale of the coupling of residue-specific charge probability distributions in these proteins. While some nonpolar residues exhibit expectedly narrow charge distributions, most polar and charged residues exhibit broad, multimodal distributions. Even for nonpolar residues, we observe sequence-specific deviations correspond-ing to charge accumulation or depletion that would be challenging to capture in a fixed charge force field. We quantify the effect of residue-residue interactions on charge distributions first with linear cross-correlations. We then show how additional insight can be gained from evaluating the mutual information of charge distributions. We show that a significant number of residues couple most strongly with residues that are distant in both sequence and space over a range of secondary structures including α-helical, β-sheet, disulfide bridging, and lasso motifs. The mutual information analysis is necessary to capture coupling between some polar and charged residues that would be otherwise missed.

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Gauging the Flexibility of the Active Site in Soybean Lipoxygenase-1 (SLO-1) through an Atom-Centered Density Matrix Propagation (ADMP) Treatment That Facilitates the Sampling of Rare Events

Cited by 31 publications

References 204 publications

Active Site Dynamical Effects in the Hydrogen Transfer Rate-limiting Step in the Catalysis of Linoleic Acid by Soybean Lipoxygenase-1 (SLO-1): Primary and Secondary Isotope Contributions

Active Site Dynamical Effects in the Hydrogen Transfer Rate-limiting Step in the Catalysis of Linoleic Acid by Soybean Lipoxygenase-1 (SLO-1): Primary and Secondary Isotope Contributions

Protein effects in non-heme iron enzyme catalysis: insights from multiscale models

Quantifying the Long‐Range Coupling of Electronic Properties in Proteins with ab initio Molecular Dynamics**

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