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Mats H M Olsson

Publications and source records attributed to Mats H M Olsson.

9 recordsLinked to original sources
PubMed2006

Transition state theory can be used in studies of enzyme catalysis: lessons from simulations of tunnelling and dynamical effects in lipoxygenase and other systems.

The idea that enzyme catalysis involves special factors such as coherent fluctuations, quantum mechanical tunnelling and non-equilibrium solvation (NES) effects has gained popularity in recent years. It has also been suggested that transition state theory (TST) cannot be used in studies of enzyme catalysis. The present work uses reliable state of the art simulation approaches to examine the above ideas. We start by demonstrating that we are able to simulate any of the present catalytic proposals using the empirical valence bond (EVB) potential energy surfaces, the dispersed polaron model and the quantized classical path (QCP) approach, as well as the approximate vibronic method. These approaches do not treat the catalytic effects by phenomenological treatments and thus can be considered as first principles approaches (at least their ability to compare enzymatic reaction to the corresponding solution reactions). This work will consider the lipoxygenase reaction, and to lesser extent other enzymes, for specific demonstration. It will be pointed out that our study of the lipoxygenase reaction reproduces the very large observed isotope effect and the observed rate constant while obtaining no catalytic contribution from nuclear quantum mechanical (NQM) effects. Furthermore, it will be clarified that our studies established that the NQM effect decreases rather than increases when the donor-acceptor distance is compressed. The consequences of these findings in terms of the temperature dependence of the kinetic isotope effect and in terms of different catalytic proposals will be discussed. This paper will also consider briefly the dynamical effects and conclude that such effects do not contribute in a significant way to enzyme catalysis. Furthermore, it will be pointed out that, in contrast to recent suggestions, NES effects are not dynamical effects and should therefore be part of the activation free energy rather than the transmission factor. In view of findings of the present work and our earlier works, it seems that TST provides a quantitative tool for studies of enzyme catalysis and that the key open questions are related to the nature of the factors that lead to transition state stabilization.

Catalysis↗
PubMed2006

Monte Carlo simulations of proton pumps: on the working principles of the biological valve that controls proton pumping in cytochrome c oxidase.

Gaining a detailed understanding of the proton-pumping process in cytochrome c oxidase (COX) is one of the challenges of modern biophysics. Recent mutation experiments have highlighted this challenge by showing that a single mutation (the N139D mutation) blocks the overall pumping while continuing to channel protons to the binuclear center without inhibiting the oxidase activity. Rationalizing this result has been a major problem because the mutation is quite far from E286, which is believed to serve as the branching point for the proton transport in the pumping process. In the absence of a reasonable explanation for this important observation, we have developed a Monte Carlo simulation method that can convert mutation and structural information to pathways for proton translocation and simulate the pumping process in COX on a millisecond and even subsecond time scale. This tool allows us to reproduce and propose a possible explanation to the effect of the N139D mutation and to offer a consistent model for the origin of the "valve effect" in COX, which is crucial for maintaining uphill proton pumping. Furthermore, obtaining the first structure-based simulation of proton pumping in COX, or in any other protein, indicates that our approach should provide a powerful tool for verification of mechanistic hypotheses about the action of proton transport proteins.

Biophysical Phenomena↗
PubMed2005

Simulating redox coupled proton transfer in cytochrome c oxidase: looking for the proton bottleneck.

Gaining a detailed understanding of the molecular nature of the redox coupled proton transfer in cytochrome c oxidase (COX) is one of the challenges of modern biophysics. The present work addresses this by integrating approaches for simulations of proton transport (PTR) and electron transfer (ET). The resulting method converts the electrostatic energies of different charge configurations and reorganization energies to free-energy profiles for different PTR and ET pathways. This approach provides for the first time a tool to study the actual activation barriers and kinetics of different feasible PTR processes in the cycle of COX. Using this tool, we explore the PTR through the bottleneck water molecules. It is found that a stepwise PTR along this commonly assumed path leads to far too high barriers and is, thus, inconsistent with the observed kinetics. Furthermore, the simulated free-energy profile does not provide a simple gating mechanism. Fortunately, we obtain reasonable kinetics when we consider a PTR that involves a concerted transfer of protons to and from E286. Finally, semi-qualitative considerations of the forward and backward barriers point toward open questions about the actual gating process and offer a feasible pumping mechanism. Although further studies are clearly needed, we believe that our approach offers a general and effective tool for correlating the structure of COX with its function.

Electron Transport Complex IV↗
PubMed2004

Solute solvent dynamics and energetics in enzyme catalysis: the S(N)2 reaction of dehalogenase as a general benchmark.

One of the most useful ways of describing and analyzing enzyme catalysis is the description of the enzyme as an effective solvent for the reacting substrate. Here, we illustrate this concept by considering the S(N)2 reaction of haloalkan dehalogenase (DhlA), analyze the energetics and dynamics of the solvent coordinate, and evaluate their relative catalytic effect. It is demonstrated that almost the entire catalytic effect is associated with the preorganization of the protein-solvent coordinate. It is clarified that this effect is associated with the fact that the transition state is "solvated" by the protein more than in the reference solution reaction. This effect is fundamentally different than the frequently proposed desolvation mechanism. The possible catalytic role of dynamical effects is analyzed by considering several reasonable ways of defining "dynamical contributions to catalysis". It is found that these contributions are small regardless of the definition used. It is also shown that the effect of the difference in the relaxation time of the solvent coordinate in the enzyme and solution reaction is rather trivial relative to the effect of the corresponding changes in reorganization free energy.

Catalysis↗
PubMed2004

Simulations of the large kinetic isotope effect and the temperature dependence of the hydrogen atom transfer in lipoxygenase.

Elucidating the role of nuclear quantum mechanical (NQM) effects in enzyme catalysis is a topic of significant current interest. Despite the great experimental progress in this field it is important to have theoretical approaches capable of evaluating and analyzing nuclear quantum mechanical contributions to catalysis. In this study, we use the catalytic reaction of lipoxygenase, which is characterized by an extremely large kinetic isotope effect, as a challenging test case for our simulation approach. This is done by applying the quantum classical path (QCP) method with an empirical valence bond potential energy surface. Our computational strategy evaluates the relevant NQM corrections and reproduces the large observed kinetic isotope effect and the temperature dependence of the H atom transfer reaction while being less successful with the D atom transfer reaction. However, the main point of our study is not so much to explore the temperature dependence of the isotope effect but rather to develop and validate an approach for calculations of nuclear quantum mechanical contributions to activation free energies. Here, we find that the deviation between the calculated and observed activation free energies is small for both H and D at all investigated temperatures. The present study also explores the nature of the reorganization energy in the enzyme and solution reactions. It is found that the outer-sphere reorganization energy is extremely small. This reflects the fact that the considered reaction involves a very small charge transfer. The implication of this finding is discussed in the framework of the qualitative vibronic model. The main point of the present study is, however, that the rigorous QCP approach provides a reliable computational tool for evaluating NQM contributions to catalysis even when the given reaction includes large tunneling contributions. Interestingly, our results indicate that the NQM effects in the lipoxygenase reaction are similar in the enzyme and in the reference solution reactions, and thus do not contribute to catalysis. We also reached similar conclusions in studies of other enzymes.

Computer Simulation↗
PubMed2003

Simulating large nuclear quantum mechanical corrections in hydrogen atom transfer reactions in metalloenzymes.

The role of nuclear quantum mechanical effects in enzyme catalysis has recently attracted significant interest both from theoretical and experimental points of view. From a theoretical point of view, it is undoubtedly a challenge to try to account for the observed tunneling in the protein by microscopic simulations without adjustable parameters. One of the most spectacular examples of nuclear quantum mechanical effects is the reaction of lipoxygenase, which is characterized by a very large kinetic isotope effect and, thus, provides an excellent benchmark for simulation approaches. In the present study, we report a microscopic simulation of the large kinetic isotope effect in soybean lipoxygenase and its temperature dependence. This is, to the best of our knowledge, the first time that a very large nuclear quantum mechanical contribution to the activation free energy of a hydrogen atom transfer reaction and its temperature dependence have been evaluated by microscopic simulation. The simulation reproduces quite well the experimental kinetic information and the corresponding difference between the classical and quantum mechanical activation free energies for the H and D transfer reactions.

Catalysis↗
PubMed2003

Frozen density functional free energy simulations of redox proteins: computational studies of the reduction potential of plastocyanin and rusticyanin.

The evaluation of reduction potentials of proteins by ab initio approaches presents a major challenge for computational chemistry. This is addressed in the present investigation by reporting detailed calculations of the reduction potentials of the blue copper proteins plastocyanin and rusticyanin using the QM/MM all-atom frozen density functional theory, FDFT, method. The relevant ab initio free energies are evaluated by using a classical reference potential. This approach appears to provide a general consistent and effective way for reproducing the configurational ensemble needed for consistent ab initio free energy calculations. The FDFT formulation allows us to treat a large part of the protein quantum mechanically by a consistently coupled QM/QM/MM embedding method while still retaining a proper configurational sampling. To establish the importance of proper configurational sampling and the need for a complete representation of the protein+solvent environment, we also consider several classical approaches. These include the semi-macroscopic PDLD/S-LRA method and classical all-atom simulations with and without a polarizable force field. The difference between the reduction potentials of the two blue copper proteins is reproduced in a reasonable way, and its origin is deduced from the different calculations. It is found that the protein permanent dipole tunes down the reduction potential for plastocyanin compared to the active site in regular water solvent, whereas in rusticyanin it is instead tuned up. This electrostatic environment, which is the major effect determining the reduction potential, is a property of the entire protein and solvent system and cannot be ascribed to any particular single interaction.

Azurin↗