Microsecond timescale MD simulations at the transition state of <i>Pm</i>HMGR predict remote allosteric residues

Quinn, Taylor R.; Steussy, C.N.; Haines, Brandon E.; Lei, Jinping; Wang, Wei; Sheong, Fu Kit; Stauffacher, Cynthia V.; Huang, Xuhui; Norrby, Per‐Ola; Helquist, Paul; Wiest, Olaf

doi:10.1039/d1sc00102g

Cited by 7 publications

(6 citation statements)

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“…A positively charged imidazole ring of His381 orients away from Ser85 and toward the thiolate to stabilize the negative charge while maintaining the electrostatic interactions with the ribose of NADH. For the Pm HMGR active site, the thiohemiacetal decomposition has a barrier of about 7 kcal/mol, and the mechanism discussed here can serve as a model for other similar catalytic sites such as fatty alcohol forming fatty acyl-CoA reductase. ,, The results described here will also serve as a starting point for the development of transition state force fields that allow microsecond MD simulations at the transition state of a reaction to study larger-scale changes of the protein structure to stabilize the transition state. , …”

Section: Discussionmentioning

confidence: 99%

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Computational Study of Base-Catalyzed Thiohemiacetal Decomposition in Pseudomonas mevalonii HMG-CoA Reductase

et al. 2023

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Thiohemiacetals are key intermediates in the active sites of many enzymes catalyzing a variety of reactions. In the case of Pseudomonas mevalonii 3-hydroxy-3-methylglutaryl coenzyme A reductase (PmHMGR), this intermediate connects the two hydride transfer steps where a thiohemiacetal is the product of the first hydride transfer and its breakdown forms the substrate of the second one, serving as the intermediate during cofactor exchange. Despite the many examples of thiohemiacetals in a variety of enzymatic reactions, there are few studies that detail their reactivity. Here, we present computational studies on the decomposition of the thiohemiacetal intermediate in PmHMGR using both QM-cluster and QM/MM models. This reaction mechanism involves a proton transfer from the substrate hydroxyl to an anionic Glu83 followed by a C−S bond elongation stabilized by a cationic His381. The reaction provides insight into the varying roles of the residues in the active site that favor this multistep mechanism.

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Section: Discussionmentioning

confidence: 99%

“…16,67,68 The results described here will also serve as a starting point for the development of transition state force fields that allow microsecond MD simulations at the transition state of a reaction to study larger-scale changes of the protein structure to stabilize the transition state. 70…”

Section: ■ Conclusionmentioning

confidence: 99%

Computational Study of Base-Catalyzed Thiohemiacetal Decomposition in Pseudomonas mevalonii HMG-CoA Reductase

et al. 2023

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“…The results presented here are an early example for using exclusively electronic structure reference data and a much larger number of parameters adjusted in the biomolecular TSFF than in the earlier cases of small molecule TSFFs [ 25 , 26 ] and the derivation of docking potentials [ 39 , 40 ] using Q2MM. They show that the Q2MM approach can be used to parameterize a TSFF to simulate enzymes at the transition state ~10 4 times faster than the underlying electronic structure methods, allowing for molecular dynamics simulation for system sizes and timescales well beyond the accessibility of DFT-based methods [ 64 ].…”

Section: Discussionmentioning

confidence: 99%

“…As shown in Fig 3B , the TSFF successfully reproduced the geometries around the reacting center of the active site and could successfully be incorporated into the rest of the enzyme that is treated with a traditional ground state force field. Using this, the enzyme could be simulated at the transition state on the microsecond timescale [ 64 ].…”

Section: Application To Pm Hmgrmentioning

confidence: 99%

Automated fitting of transition state force fields for biomolecular simulations

et al. 2022

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The generation of surrogate potential energy functions (PEF) that are orders of magnitude faster to compute but as accurate as the underlying training data from high-level electronic structure methods is one of the most promising applications of fitting procedures in chemistry. In previous work, we have shown that transition state force fields (TSFFs), fitted to the functional form of MM3* force fields using the quantum guided molecular mechanics (Q2MM) method, provide an accurate description of transition states that can be used for stereoselectivity predictions of small molecule reactions. Here, we demonstrate the applicability of the method for fit TSFFs to the well-established Amber force field, which could be used for molecular dynamics studies of enzyme reaction. As a case study, the fitting of a TSFF to the second hydride transfer in Pseudomonas mevalonii 3-hydroxy-3-methylglutaryl coenzyme A reductase (PmHMGR) is used. The differences and similarities to fitting of small molecule TSFFs are discussed.

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“…By reducing the model resolution, the computational cost and the configuration space of the system decrease, thus enabling the modeling of larger and more complex systems compared to atomistic simulations. For some phenomena, such as the conformation change of enzymes and functional proteins, , the limiting factor of all-atom (AA) simulations is the timescale needed to witness a specific process. In this regard, CG models enable longer timesteps and thus accessible simulation times by suppressing the high-frequency motion characteristics of light atoms and/or averaging out some intramolecular degrees of freedom.…”

Section: Introductionmentioning

confidence: 99%

Anisotropic Electrostatic Interactions in Coarse-Grained Water Models to Enhance the Accuracy and Speed-Up Factor of Mesoscopic Simulations

Bellussi

Roscioni²,

Ricci³

et al. 2021

J. Phys. Chem. B

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Water models with realistic physical–chemical properties are essential to study a variety of biomedical processes or engineering technologies involving molecules or nanomaterials. Atomistic models of water are constrained by the feasible computational capacity, but calibrated coarse-grained (CG) ones can go beyond these limits. Here, we compare three popular atomistic water models with their corresponding CG model built using finite-size particles such as ellipsoids. Differently from previous approaches, short-range interactions are accounted for with the generalized Gay–Berne potential, while electrostatic and long-range interactions are computed from virtual charges inside the ellipsoids. Such an approach leads to a quantitative agreement between the original atomistic models and their CG counterparts. Results show that a timestep of up to 10 fs can be achieved to integrate the equations of motion without significant degradation of the physical observables extracted from the computed trajectories, thus unlocking a significant acceleration of water-based mesoscopic simulations at a given accuracy.

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Microsecond timescale MD simulations at the transition state of PmHMGR predict remote allosteric residues

Abstract: Understanding the mechanisms of enzymatic catalysis requires a detailed understanding of the complex interplay of structure and dynamics of large systems that is a challenge for both experimental and computational...

Cited by 7 publications

References 29 publications

Computational Study of Base-Catalyzed Thiohemiacetal Decomposition in Pseudomonas mevalonii HMG-CoA Reductase

Computational Study of Base-Catalyzed Thiohemiacetal Decomposition in Pseudomonas mevalonii HMG-CoA Reductase

Automated fitting of transition state force fields for biomolecular simulations

Anisotropic Electrostatic Interactions in Coarse-Grained Water Models to Enhance the Accuracy and Speed-Up Factor of Mesoscopic Simulations

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