Insights from Microbial Transition State Theory on Monod's Affinity Constant.
Ontology highlight
ABSTRACT:
SUBMITTER: Ugalde-Salas P
PROVIDER: S-EPMC7093443 | biostudies-literature | 2020 Mar
REPOSITORIES: biostudies-literature
Publications
Insights from Microbial Transition State Theory on Monod's Affinity Constant.
Ugalde-Salas Pablo P Desmond-Le Quéméner Elie E Harmand Jérôme J Rapaport Alain A Bouchez Théodore T
Scientific reports 20200324 1
Microbial transition state theory (MTS) offers a theoretically explicit mathematical model for substrate limited microbial growth. By considering a first order approximation of the MTS equation one recovers the well-known Monod's expression for growth, which was regarded as a purely empirical function. The harvest volume of a cell as defined in MTS theory can then be related to the affinity concept, giving a new physical interpretation to it, and a new way to determine its value. Consequences of ...[more]
Similar Datasets
Project description:We describe and test on some organic reactions a parallel implementation strategy to compute anharmonic constants, which are employed in semiclassical transition state theory reaction rate calculations. Our software can interface with any quantum chemistry code capable of a single point energy estimate, and it is suitable for both minimum and transition state geometry calculations. After testing the accuracy and comparing the efficiency of our implementation against other software, we use it to estimate the semiclassical transition state theory (SCTST) rate constant of three reactions of increasing dimensionality, known as examples of heavy atom tunneling. We show how our method is improved in efficiency with respect to other existing implementations. In conclusion, our approach allows SCTST rates and heavy atom tunneling at a high level of electronic structure theory (up to CCSD(T)) to be evaluated. This work shows how crucial the possibility to perform high level ab initio rate evaluations can be.
| S-EPMC8830048 | biostudies-literature
Project description:While being one of the most popular reaction rate theories, the applicability of transition state theory to the study of enzymatic reactions has been often challenged. The complex dynamic nature of the protein environment raised the question about the validity of the nonrecrossing hypothesis, a cornerstone in this theory. We present a computational strategy to quantify the error associated to transition state theory from the number of recrossings observed at the equicommittor, which is the best possible dividing surface. Application of a direct multidimensional transition state optimization to the hydride transfer step in human dihydrofolate reductase shows that both the participation of the protein degrees of freedom in the reaction coordinate and the error associated to the nonrecrossing hypothesis are small. Thus, the use of transition state theory, even with simplified reaction coordinates, provides a good theoretical framework for the study of enzymatic catalysis.
| S-EPMC5703300 | biostudies-literature
Project description:Deprotonation of the alkoxysulfonium intermediate has been shown to be rate-determining in the Swern oxidation of benzyl alcohol. Directly following this rate-determining step is the intramolecular syn-?-elimination of the ylide. In the present study, intramolecular (2)H kinetic isotope effects (KIEs) are used to gain insight into this syn-?-elimination step. As a result of the stereogenic sulfur center in the ylide intermediate, two diastereomeric transition states (endo-TS1 and exo-TS1) must be assumed to contribute to the intramolecular KIE. The intramolecular (2)H KIE determined at -78 °C is 2.82 ± 0.06. Attempts to reproduce this measurement computationally using transition state theory and a Bell tunneling correction yielded a value (1.58) far below that determined experimentally. Computational analysis is complicated by the existence of two distinct transition structures owing to the stereogenic center. Two extremes of Curtin-Hammett kinetics are explored using energies, vibrational frequencies, and moments of inertia from computed transition structures. Neither Curtin-Hammett scenario can reproduce the observed KIE to any acceptable degree of fidelity. Evidence based upon previous kinetics measurements and calculations upon a model system suggests that the stereogenic sulfur center is not likely to undergo inversion to a significant degree at the temperatures at which the Swern oxidation is performed here. Proceeding under the assumption of no stereoinversion at the sulfur center, calculations predict a nearly linear Arrhenius plot for the KIE--even with the inclusion of a one-dimensional tunneling correction. By contrast, the experimentally determined temperature dependence shows a significant concave upward curvature indicative of the influence of tunneling. Notably, KIEs measured in CCl(4), CHCl(3), CH(2)Cl(2), dichloroethane, and chlorobenzene at -23 °C showed little variance. This finding discounted the possible influence from dynamical effects due to incomplete vibrational relaxation. An ad hoc amplification of the imaginary frequencies corresponding to the first-order saddle points corresponding to endo-TS1 and exo-TS1 allowed us to reproduce the experimental temperature dependence of the KIE using only two adjustable parameters applied to a kinetic scenario that involves four isotopomeric transition states. The cumulative data and computational modeling strongly suggest that, even though the intramolecular (2)H KIE observed in these experiments is small, this reaction requires a multidimensional description of the tunneling phenomenon to accurately reproduce experimental trends.
| S-EPMC2995308 | biostudies-literature
Project description:Transition state theory fails to accurately predict the selectivity in an example where it is ubiquitously invoked, hydroboration. The hydroboration of terminal alkenes with BH(3) is moderately regioselective, affording an 88:12-90:10 ratio of anti-Markovnikov/Markovnikov adducts. High-level ab initio calculations predict too large of an energy difference between anti-Markovnikov and Markovnikov transition structures to account for the observed product ratio, and consideration of calculational error, solvent, tunneling, and entropy effects does not resolve the discrepancy. Trajectory studies, however, predict well the experimental selectivity. The decreased selectivity versus transition state theory arises from the excess energy generated as the BH(3) interacts with the alkene, and the observed selectivity is proposed to result from a combination of low selectivity in direct trajectories, moderate RRKM selectivity, and high selectivity after thermal equilibration.
| S-EPMC2880641 | biostudies-literature
Project description:BackgroundMulti-state models are being increasingly used to capture complex disease pathways. The convenient formula of the exponential multi-state model can facilitate a quick and accessible understanding of the data. However, assuming time constant transition rates is not always plausible. On the other hand, obtaining predictions from a fitted model with time-dependent transitions can be challenging. One proposed solution is to utilise a general simulation algorithm to calculate predictions from a fitted multi-state model.MethodsPredictions obtained from an exponential multi-state model were compared to those obtained from two different parametric models and to non-parametric Aalen-Johansen estimates. The first comparative approach fitted a multi-state model with transition-specific distributions, chosen separately based on the Akaike Information Criterion. The second approach was a Royston-Parmar multi-state model with 4 degrees of freedom, which was chosen as a reference model flexible enough to capture complex hazard shapes. All quantities were obtained analytically for the exponential and Aalen-Johansen approaches. The transition rates for the two comparative approaches were also obtained analytically, while all other quantities were obtained from the fitted models via a general simulation algorithm. Metrics investigated were: transition probabilities, attributable mortality (AM), population attributable fraction (PAF) and expected length of stay. This work was performed on previously analysed hospital acquired infection (HAI) data. By definition, a HAI takes three days to develop and therefore selected metrics were also predicted from time 3 (delayed entry).ResultsDespite clear deviations from the constant transition rates assumption, the empirical estimates of the transition probabilities were approximated reasonably well by the exponential model. However, functions of the transition probabilities, e.g. AM and PAF, were not well approximated and the comparative models offered considerable improvements for these metrics. They also provided consistent predictions with the empirical estimates in the case of delayed entry time, unlike the exponential model.ConclusionWe conclude that methods and software are readily available for obtaining predictions from multi-state models that do not assume constant transition rates. The multistate package in Stata facilitates a range of predictions with confidence intervals, which can provide a more comprehensive understanding of the data. User-friendly code is provided.
| S-EPMC7798316 | biostudies-literature
Project description:Experiments show that for many two-state folders the free energy of the native state, DeltaG(ND)([C]), changes linearly as the denaturant concentration, [C], is varied. The slope {m = [dDeltaG(ND)([C])]/(d[C])}, is nearly constant. According to the transfer model, the m-value is associated with the difference in the surface area between the native (N) and denatured (D) state, which should be a function of DeltaR(g)(2), the difference in the square of the radius of gyration between the D and N states. Single-molecule experiments show that the R(g) of the structurally heterogeneous denatured state undergoes an equilibrium collapse transition as [C] decreases, which implies m also should be [C]-dependent. We resolve the conundrum between constant m-values and [C]-dependent changes in R(g) using molecular simulations of a coarse-grained representation of protein L, and the molecular transfer model, for which the equilibrium folding can be accurately calculated as a function of denaturant (urea) concentration. In agreement with experiment, we find that over a large range of denaturant concentration (>3 M) the m-value is a constant, whereas under strongly renaturing conditions (<3 M), it depends on [C]. The m-value is a constant above [C] > 3 M because the [C]-dependent changes in the surface area of the backbone groups, which make the largest contribution to m, are relatively narrow in the denatured state. The burial of the backbone and hydrophobic side chains gives rise to substantial surface area changes below [C] < 3 M, leading to collapse in the denatured state of protein L. Dissection of the contribution of various amino acids to the total surface area change with [C] shows that both the sequence context and residual structure are important. There are [C]-dependent variations in the surface area for chemically identical groups such as the backbone or Ala. Consequently, the midpoints of transition of individual residues vary significantly (which we call the Holtzer effect) even though global folding can be described as an all-or-none transition. The collapse is specific in nature, resulting in the formation of compact structures with appreciable populations of nativelike secondary structural elements. The collapse transition is driven by the loss of favorable residue-solvent interactions and a concomitant increase in the strength of intrapeptide interactions with a decreasing [C]. The strength of these interactions is nonuniformly distributed throughout the structure of protein L. Certain secondary structure elements have stronger [C]-dependent interactions than others in the denatured state.
| S-EPMC5551902 | biostudies-literature
Project description:Prospect Theory (PT) and Constant-Relative-Risk-Aversion (CRRA) preferences have clear-cut and very different implications for the optimal asset allocation between a riskless asset and a risky stock as a function of the investment horizon. While CRRA implies that the optimal allocation is independent of the horizon, we show that PT implies a dramatic and discontinuous "jump" in the optimal allocation as the horizon increases. We experimentally test these predictions at the individual level. We find rather strong support for CRRA, but very little support for PT.
| S-EPMC8016345 | biostudies-literature
Project description:6-Hydroxymethyl-7,8-dihydropterin pyrophosphokinase (HPPK) is a key enzyme in the folate biosynthesis pathway. It catalyzes pyrophosphoryl transfer from ATP to 6-hydroxymethyl-7,8-dihydropterin (HP). HPPK is essential for microorganisms but absent in mammals; therefore, it is an attractive target for developing novel antimicrobial agents. Previously, based on our studies of the structure and mechanism of HPPK, we created first-generation bisubstrate inhibitors by linking 6-hydroxymethylpterin to adenosine through phosphate groups, and developed second-generation inhibitors by replacing the phosphate bridge with a linkage that contains a piperidine moiety. Here, we report third-generation inhibitors designed based on the piperidine-containing inhibitor, mimicking the transition state. We synthesized two such inhibitors, characterized their protein-binding and enzyme inhibition properties, and determined their crystal structures in complex with HPPK, advancing the development of such bisubstrate analog inhibitors.
| S-EPMC7855645 | biostudies-literature
Project description:Although previous studies have described opposing states in upwelling regions, i.e., the rise of cold nutrient-rich waters and prevalence of surface warm nutrient-poor waters, few have addressed the transition from one state to the other. This study aimed to describe the microbial and viral structure during this transition and was able to obtain the taxonomic and metabolic compositions as well as physical-chemical data. This integrated approach allowed for a better understanding of the dynamics of the downwelling upwelling transition, suggesting that a wealth of metabolic processes and ecological interactions are occurring in the minute fractions of the plankton (femto, pico, nano). These processes and interactions included evidence of microbial predominance during downwelling (with nitrogen recycling and aerobic anoxygenic photosynthesis), different viral predation pressures over primary production in different states (cyanobacteria vs eukaryotes), and a predominance of diatoms and selected bacterial and archaeal groups during upwelling (with the occurrence of a wealth of nitrogen metabolism involving ammonia). Thus, the results provided insights into which microbes, viruses and microbial-mediated processes are probably important in the functioning of upwelling systems.
| S-EPMC4556663 | biostudies-literature
Project description:This manuscript describes ongoing research on the nature of chemical reactions in enzymes. We will investigate how protein dynamics can couple to chemical reaction in an enzyme. We first investigate in some detail why transition state theory cannot fully describe the dynamics of chemical reactions catalysed by enzymes. We describe quantum theories of chemical reaction in condensed phase including studies of how the symmetry of coupled vibrational modes differentially affects reaction dynamics. We make reference to previous work in our group on a variety of condensed phase chemical reactions (liquid and crystalline) and a variety of enzymatically catalysed reactions including the reactions of lactate dehydrogenase and purine nucleoside phosphorylase. All the protein motions we have studied have been quite rapid. We will propose methods to find motions over a broad range of time-scales in enzymes that couple to chemical catalysis. We report recent findings which show that conformational fluctuations in lactate dehydrogenase can strongly affect its ability to catalyse reactions through protein motion, and that only a tiny minority of conformations appear to be catalytically competent.
| S-EPMC1647311 | biostudies-literature