Biomedical subjects

Edina Rosta

Publications and source records attributed to Edina Rosta.

6 recordsLinked to original sources

PubMed2006

On the mechanism of hydrolysis of phosphate monoesters dianions in solutions and proteins.

The nature of the hydrolysis of phosphate monoester dianions in solutions and in proteins is a problem of significant current interest. The present work explores this problem by systematic calculations of the potential surfaces of the reactions of a series of phosphate monoesters with different leaving groups. These calculations involve computational studies ranging from ab initio calculations with implicit solvent models to ab initio QM/MM free energy calculations. The calculations reproduce the observed linear free energy relationship (LFER) for the solution reaction and thus are consistent with the overall experimental trend and can be used to explore the nature of the transition state (TS) region, which is not accessible to direct experimental studies. It is found that the potential surface for the associative and dissociative paths is very flat and that the relative height of the associative and dissociative TS is different in different systems. In general, the character of the TS changes from associative to dissociative upon decrease in the pKa of the leaving group. It is also demonstrated that traditional experimental markers such as isotope effects and the LFER slope cannot be used in a conclusive way to distinguish between the two classes of transition states. In addition it is found that the effective charges of the TS do not follow the previously assumed simple rule. Armed with that experience we explore the free energy surface for the GTPase reaction of the RasGap system. In this case it is found that the surface is flat but that the lowest TS is associative. The present study indicates that the nature of the potential surfaces for the phosphoryl transfer reactions in solution and proteins is quite complicated and cannot be determined in a conclusive way without the use of careful theoretical studies that should, of course, reproduce the available experimental information.

GTPase-Activating Proteins↗

PubMed2006

Extending the mirror neuron system model, I. Audible actions and invisible grasps.

The paper introduces mirror neuron system II (MNS2), a new version of the MNS model (Oztop and Arbib in Biol Cybern 87 (2):116-140, 2002) of action recognition learning by mirror neurons of the macaque brain. The new model uses a recurrent architecture that is biologically more plausible than that of the original model. Moreover, MNS2 extends the capacity of the model to address data on audio-visual mirror neurons and on the response of mirror neurons when the target object was recently visible but is currently hidden.

Animals↗

PubMed2006

Using the constrained DFT approach in generating diabatic surfaces and off diagonal empirical valence bond terms for modeling reactions in condensed phases.

The empirical valence bond (EVB) model provides an extremely powerful way for modeling and analyzing chemical reactions in solutions and proteins. However, this model is based on the unverified assumption that the off diagonal elements of the EVB Hamiltonian do not change significantly upon transfer of the reacting system from one phase to another. This ad hoc assumption has been rationalized by its consistency with empirically observed linear free energy relationships, as well as by other qualitative considerations. Nevertheless, this assumption has not been rigorously established. The present work explores the validity of the above EVB key assumption by a rigorous numerical approach. This is done by exploiting the ability of the frozen density functional theory (FDFT) and the constrained density functional theory (CDFT) models to generate convenient diabatic states for QM/MM treatments, and thus to examine the relationship between the diabatic and adiabatic surfaces, as well as the corresponding effective off diagonal elements. It is found that, at least for the test case of S(N)()2 reactions, the off diagonal element does not change significantly upon moving from the gas phase to solutions and thus the EVB assumption is valid and extremely useful.

Algorithms↗

PubMed2006

Advances in methods and algorithms in a modern quantum chemistry program package.

Advances in theory and algorithms for electronic structure calculations must be incorporated into program packages to enable them to become routinely used by the broader chemical community. This work reviews advances made over the past five years or so that constitute the major improvements contained in a new release of the Q-Chem quantum chemistry package, together with illustrative timings and applications. Specific developments discussed include fast methods for density functional theory calculations, linear scaling evaluation of energies, NMR chemical shifts and electric properties, fast auxiliary basis function methods for correlated energies and gradients, equation-of-motion coupled cluster methods for ground and excited states, geminal wavefunctions, embedding methods and techniques for exploring potential energy surfaces.

Algorithms↗

PubMed2006

Towards accurate ab initio QM/MM calculations of free-energy profiles of enzymatic reactions.

Reliable studies of enzymatic reactions by combined quantum mechanical/molecular mechanics (QM/MM) approaches, with an ab initio description of the quantum region, presents a major challenge to computational chemists. The main problem is the need for a large amount of computer time to evaluate the QM energy, which in turn makes it extremely challenging to perform proper configurational sampling. This work presents major progress toward the evaluation of ab initio QM/MM free-energy surfaces and activation free energies of reactions in enzymes and in solutions. This is done by exploiting our previous idea of using the empirical valence bond (EVB) method as a reference potential and then using the linear response approximation (LRA) approach to evaluate the free energies of transfer from the EVB to the QM/MM surfaces in the reactant and product state. However, the new crucial step involves the use of a constraint at the transition state that fixes the system at a given value of the reaction coordinate and allows us to use the LRA at the transition state. The advance offered by the present approach is particularly significant because it evaluates the free energy associated with both the substrate and the solvent motions. This evaluation appeared to be a relatively simple task once one uses a classical reference potential. The main problem has been using the reference potential for the evaluation of the free-energy contributions associated with the solute motions where the difference between the reference EVB potential and the QM/MM potential can be large. The present refinement finally allows us to overcome the problems with the solute fluctuations and therefore to obtain, for the first time, a free-energy barrier that reflects the solute entropy properly. Thus, we present a way to evaluate the complete QM/MM activation free energy with an equal footing treatment of the solute and the solvent. This provides a general consistent and effective strategy for evaluating the QM/MM activation free energies in proteins and in solution. Our advance allows one to explore consistently various mechanistic and catalytic proposals while using ab initio (ai) QM/MM approaches.

Computer Simulation↗

PubMed2005

On possible pitfalls in ab initio quantum mechanics/molecular mechanics minimization approaches for studies of enzymatic reactions.

Reliable studies of enzymatic reactions by combined quantum mechanics/molecular mechanics (QM/MM) approaches, with an ab initio description of the quantum region, presents a major challenge to computational chemists. The main problem is the need for a very large computer time for the evaluation of the QM energy, which in turn makes it extremely challenging to perform proper configurational sampling. A seemingly reasonable alternative is to perform energy minimization studies of the type used in gas-phase ab initio studies. However, it is hard to see why such an approach should give reliable results in protein active sites. To examine the problems with energy minimization QM/MM approaches, we chose the hypothetical reaction of a metaphosphate ion with water in the Ras.GAP complex. This hypothetical reaction served as a simple benchmark reaction. The possible problems with the QM/MM minimization were explored by generating several protein configurations from long MD simulations and using energy minimization and scanning of the reaction coordinates to evaluate the corresponding potential energy surfaces of the reaction for each of these different protein configurations. Comparing these potential energy surfaces, we found major variations of the corresponding minima. Furthermore, the reaction energies and activation energies also varied significantly even for similar protein configurations. The specific coordination of a magnesium ion, present in the active center of the protein complex, turned out to influence the energetics of the reaction in a major way, where a direct coordination to the reactant leads to an increase of the activation energy by 17 kcal/mol. Apparently, using energy minimization to generate potential surfaces for an enzymatic reaction, while starting from a single protein structure, could lead to major errors in calculations of activation free energies and binding free energies. Thus we believe that extensive samplings of the configurational space of the protein are essential for meaningful determination of the energetics of enzymatic reactions. The possible relevance of our conclusion with regard to a recent study of the RasGAP reaction is discussed.

Computational Biology↗