scholarly journals Hydride transfer catalysed by Escherichia coli and Bacillus subtilis dihydrofolate reductase: coupled motions and distal mutations

2006 ◽  
Vol 361 (1472) ◽  
pp. 1365-1373 ◽  
Author(s):  
Sharon Hammes-Schiffer ◽  
James B Watney
Keyword(s):  
Escherichia Coli ◽  
Free Energy ◽  
Bacillus Subtilis ◽  
Dihydrofolate Reductase ◽  
Conformational Changes ◽  
Energy Barrier ◽  
Transfer Reaction ◽  
Hydride Transfer ◽  
Free Energy Barrier ◽  
Donor Acceptor

This paper reviews the results from hybrid quantum/classical molecular dynamics simulations of the hydride transfer reaction catalysed by wild-type (WT) and mutant Escherichia coli and WT Bacillus subtilis dihydrofolate reductase (DHFR). Nuclear quantum effects such as zero point energy and hydrogen tunnelling are significant in these reactions and substantially decrease the free energy barrier. The donor–acceptor distance decreases to ca 2.7 Å at transition-state configurations to enable the hydride transfer. A network of coupled motions representing conformational changes along the collective reaction coordinate facilitates the hydride transfer reaction by decreasing the donor–acceptor distance and providing a favourable geometric and electrostatic environment. Recent single-molecule experiments confirm that at least some of these thermally averaged equilibrium conformational changes occur on the millisecond time-scale of the hydride transfer. Distal mutations can lead to non-local structural changes and significantly impact the probability of sampling configurations conducive to the hydride transfer, thereby altering the free-energy barrier and the rate of hydride transfer. E. coli and B. subtilis DHFR enzymes, which have similar tertiary structures and hydride transfer rates with 44% sequence identity, exhibit both similarities and differences in the equilibrium motions and conformational changes correlated to hydride transfer, suggesting a balance of conservation and flexibility across species.

scholarly journals Confronting surface hopping molecular dynamics with Marcus theory for a molecular donor–acceptor system

2016 ◽  
Vol 195 ◽  
pp. 215-236 ◽  
Author(s):  
Jacob Spencer ◽  
Laura Scalfi ◽  
Antoine Carof ◽  
Jochen Blumberger
Keyword(s):  
Free Energy ◽  
Organic Semiconductors ◽  
Coupling Strength ◽  
Time Scale ◽  
Energy Barrier ◽  
Electronic Coupling ◽  
Free Energy Barrier ◽  
Surface Hopping ◽  
Wide Range ◽  
Donor Acceptor

We investigate the performance of fewest switches surface hopping (SH) in describing electron transfer (ET) for a molecular donor–acceptor system. Computer simulations are carried out for a wide range of reorganisation energy (λ), electronic coupling strength (Hab) and driving force using our recently developed fragment orbital-based SH approach augmented with a simple decoherence correction. This methodology allows us to compute SH ET rates over more than four orders of magnitude, from the sub-picosecond to the nanosecond time regime. We find good agreement with semi-classical ET theory in the non-adiabatic ET regime. The correct scaling of the SH ET rate with electronic coupling strength is obtained and the Marcus inverted regime is reproduced, in line with previously reported results for a spin-boson model. Yet, we find that the SH ET rate falls below the semi-classical ET rate in the adiabatic regime, where the free energy barrier is in the order of kBT in our simulations. We explain this by first signatures of non-exponential population decay of the initial charge state. For even larger electronic couplings (Hab = λ/2), the free energy barrier vanishes and ET rates are no longer defined. At this point we observe a crossover from ET on the vibronic time scale to charge relaxation on the femtosecond time scale that is well described by thermally averaged Rabi oscillations. The extension of the analysis from the non-adiabatic limit to large electronic couplings and small or even vanishing activation barriers is relevant for our understanding of charge transport in organic semiconductors.

Molecular simulations of substrate release and coupled conformational motions in adenylate kinase

2016 ◽  
Vol 15 (01) ◽  
pp. 1650004 ◽  
Author(s):  
Dachao Cui ◽  
Weitong Ren ◽  
Wenfei Li ◽  
Wei Wang
Keyword(s):  
Free Energy ◽  
Conformational Changes ◽  
Adenylate Kinase ◽  
Energy Barrier ◽  
Binding Pocket ◽  
Free Energy Barrier ◽  
Release Process ◽  
Adp Release ◽  
The One ◽  
Lid Domain

Conformational opening coupled substrate release is believed to be related to the rate limiting step in the catalysis cycle of the adenylate kinase. However, it is still unclear how the substrate dissociates from its active site and how the substrate release is coupled to conformational changes of the kinase. In this work, by using metadynamics simulations, we investigated the ADP release process and the coupled protein dynamics. We found that the ADP release involves overcoming a high free energy barrier, and protonation of the [Formula: see text]-phosphate of the ADP molecules can drastically reduce the barrier height, therefore, promote the ADP release. We identified several key residues contributing to the high free energy barrier. We also showed that the ADP attached to LID domain leaves the binding pocket earlier than the one attached to the NMP domain. We further observed that the ADP release is accompanied by almost fully opening of the LID domain and partially opening of the NMP domain. Our results provide insight into the molecular mechanism of the substrate release of adenylate kinase and the coupled conformational motions.

Molecular Basis of Glucose Transport Mechanism in Plants

2019 ◽  
Author(s):  
Balaji Selvam ◽  
Ya-Chi Yu ◽  
Liqing Chen ◽  
Diwakar Shukla
Keyword(s):  
Molecular Dynamics ◽  
Free Energy ◽  
Molecular Dynamics Simulations ◽  
Conformational Changes ◽  
Transport Mechanism ◽  
Conformational Dynamics ◽  
Site Directed Mutagenesis ◽  
Free Energy Barrier ◽  
Transport Cycle ◽  
Dynamics Simulations

<p>The SWEET family belongs to a class of transporters in plants that undergoes large conformational changes to facilitate transport of sugar molecules across the cell membrane. However, the structures of their functionally relevant conformational states in the transport cycle have not been reported. In this study, we have characterized the conformational dynamics and complete transport cycle of glucose in OsSWEET2b transporter using extensive molecular dynamics simulations. Using Markov state models, we estimated the free energy barrier associated with different states as well as 1 for the glucose the transport mechanism. SWEETs undergoes structural transition to outward-facing (OF), Occluded (OC) and inward-facing (IF) and strongly support alternate access transport mechanism. The glucose diffuses freely from outside to inside the cell without causing major conformational changes which means that the conformations of glucose unbound and bound snapshots are exactly same for OF, OC and IF states. We identified a network of hydrophobic core residues at the center of the transporter that restricts the glucose entry to the cytoplasmic side and act as an intracellular hydrophobic gate. The mechanistic predictions from molecular dynamics simulations are validated using site-directed mutagenesis experiments. Our simulation also revealed hourglass like intermediate states making the pore radius narrower at the center. This work provides new fundamental insights into how substrate-transporter interactions actively change the free energy landscape of the transport cycle to facilitate enhanced transport activity.</p>

DFT study on the hydrolysis of metsulfuron-methyl: A sulfonylurea herbicide

2018 ◽  
Vol 17 (08) ◽  
pp. 1850050 ◽  
Author(s):  
Qiuhan Luo ◽  
Gang Li ◽  
Junping Xiao ◽  
Chunhui Yin ◽  
Yahui He ◽  
...  
Keyword(s):  
Free Energy ◽  
Water Molecule ◽  
Carbonyl Group ◽  
Energy Barrier ◽  
Density Functional ◽  
Free Energy Barrier ◽  
Functional Theory ◽  
Metsulfuron Methyl ◽  
Catalytic Role ◽  
Hydrolysis Of

Sulfonylureas are an important group of herbicides widely used for a range of weeds and grasses control particularly in cereals. However, some of them tend to persist for years in environments. Hydrolysis is the primary pathway for their degradation. To understand the hydrolysis behavior of sulfonylurea herbicides, the hydrolysis mechanism of metsulfuron-methyl, a typical sulfonylurea, was investigated using density functional theory (DFT) at the B3LYP/6-31[Formula: see text]G(d,p) level. The hydrolysis of metsulfuron-methyl resembles nucleophilic substitution by a water molecule attacking the carbonyl group from aryl side (pathway a) or from heterocycle side (pathway b). In the direct hydrolysis, the carbonyl group is directly attacked by one water molecule to form benzene sulfonamide or heterocyclic amine; the free energy barrier is about 52–58[Formula: see text]kcal[Formula: see text]mol[Formula: see text]. In the autocatalytic hydrolysis, with the second water molecule acting as a catalyst, the free energy barrier, which is about 43–45[Formula: see text]kcal[Formula: see text]mol[Formula: see text], is remarkably reduced by about 11[Formula: see text]kcal[Formula: see text]mol[Formula: see text]. It is obvious that water molecules play a significant catalytic role during the hydrolysis of sulfonylureas.

scholarly journals The role of enzyme dynamics and tunnelling in catalysing hydride transfer: studies of distal mutants of dihydrofolate reductase

2006 ◽  
Vol 361 (1472) ◽  
pp. 1307-1315 ◽  
Author(s):  
Lin Wang ◽  
Nina M Goodey ◽  
Stephen J Benkovic ◽  
Amnon Kohen
Keyword(s):  
Temperature Dependence ◽  
Dihydrofolate Reductase ◽  
Isotope Effects ◽  
Hydride Transfer ◽  
Activation Parameters ◽  
Physical Nature ◽  
Enzyme Dynamics ◽  
Temperature Dependences ◽  
Donor Acceptor ◽  
Significant Temperature

Residues M42 and G121 of Escherichia coli dihydrofolate reductase ( ec DHFR) are on opposite sides of the catalytic centre (15 and 19 Å away from it, respectively). Theoretical studies have suggested that these distal residues might be part of a dynamics network coupled to the reaction catalysed at the active site. The ec DHFR mutant G121V has been extensively studied and appeared to have a significant effect on rate, but only a mild effect on the nature of H-transfer. The present work examines the effect of M42W on the physical nature of the catalysed hydride transfer step. Intrinsic kinetic isotope effects (KIEs), their temperature dependence and activation parameters were studied. The findings presented here are in accordance with the environmentally coupled hydrogen tunnelling. In contrast to the wild-type (WT), fluctuations of the donor–acceptor distance were required, leading to a significant temperature dependence of KIEs and deflated intercepts. A comparison of M42W and G121V to the WT enzyme revealed that the reduced rates, the inflated primary KIEs and their temperature dependences resulted from an imperfect potential surface pre-arrangement relative to the WT enzyme. Apparently, the coupling of the enzyme's dynamics to the reaction coordinate was altered by the mutation, supporting the models in which dynamics of the whole protein is coupled to its catalysed chemistry.

COMPARING FOLDING MECHANISMS OF DIFFERENT PRION PROTEINS BY Gō MODEL

2013 ◽  
Vol 12 (08) ◽  
pp. 1341004
Author(s):  
XUE WU ◽  
TING FU ◽  
ZHI-LONG XIU ◽  
LIU YIN ◽  
JIN-GUANG WANG ◽  
...  
Keyword(s):  
Free Energy ◽  
Prion Protein ◽  
Energy Barrier ◽  
Prion Proteins ◽  
Coarse Grained ◽  
Transmissible Spongiform Encephalopathies ◽  
Free Energy Barrier ◽  
Spongiform Encephalopathies ◽  
Go Model ◽  
Folding Free Energy

Prions are associated with neurodegenerative diseases induced by transmissible spongiform encephalopathies. The infectious scrapie form is referred to as PrP Sc , which has conformational change from normal prion with predominant α-helical conformation to the abnormal PrP Sc that is rich in β-sheet content. Neurodegenerative diseases have been found from both human and bovine sources, but there are no reports about infected by transmissible spongiform encephalopathies from rabbit, canine and horse sources. Here we used coarse-grained Gō model to compare the difference among human, bovine, rabbit, canine, and horse normal (cellular) prion proteins. The denatured state of normal prion has relation with the conversion from normal to abnormal prion protein, so we used all-atom Gō model to investigate the folding pathway and energy landscape for human prion protein. Through using coarse-grained Gō model, the cooperativity of the five prion proteins was characterized in terms of calorimetric criterion, sigmoidal transition, and free-energy profile. The rabbit and horse prion proteins have higher folding free-energy barrier and cooperativity, and canine prion protein has slightly higher folding free-energy barrier comparing with human and bovine prion proteins. The results from all-atom Gō model confirmed the validity of C α-Gō model. The correlations of our results with previous experimental and theoretical researches were discussed.

Elucidating the role of solvents in acid catalyzed dehydration of biorenewable hydroxy-lactones

2020 ◽  
Vol 5 (4) ◽  
pp. 651-662 ◽  
Author(s):  
Gourav Shrivastav ◽  
Tuhin S. Khan ◽  
Manish Agarwal ◽  
M. Ali Haider
Keyword(s):  
Free Energy ◽  
Transition State ◽  
Energy Barrier ◽  
Free Energy Barrier ◽  
Activation Free Energy ◽  
Acid Catalyzed

Utilizing the differential stabilization of reactant and transition state in the polar and apolar solvents to lower the activation free energy barrier for acid-catalyzed dehydration of hydroxy lactones.

Sign in / Sign up

Export Citation Format

Share Document