Faculty Profile
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Steven SchwartzProfessorEmail: sschwartz@email.arizona.edu Building: OC 202 Phone: 621-6363 | Honors
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Education and Appointments
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Research Interests
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Research Summary | |||
The work in my group focuses on understanding the chemistry and physics of complex chemical reactions.The overall goal of the work in my group is to produce methods and applications that explain phenomena that we cannot directly interrogate by experiment. In particular, much of our effort is focused on a wide range of biological systems. The work centers on both the development of basic new theoretical methods and application of the theoretical approaches to real systems. The research continues to result in basic additions to our understanding of the chemistry and physics of life processes. A few specific examples follow.
A major focus has been on understanding the atomic reaction coordinate of chemical reactions when catalyzed by enzymes. The reaction coordinate, as the chemical reaction traverses the transition state, is a statement of the microscopic mechanism of the reaction. Our studies have allowed us to show that in some enzymes, evolution has crafted the protein matrix of the enzyme to channel vibrational energy to reacting species. The example to the right shows just such a "promoting vibration," as we have termed it, in lactate dehydrogenase (LDH.) Compressive motion in the protein allows a donor and acceptor (lactate and cofactor NADH) to be brought into close proximity. The work that led to this discovery involved application of Transition Path Sampling (TPS) to an enzymatic reaction. The creation of an ensemble of reactive trajectories is the starting point, however, further significant analysis is needed to identify the reaction coordinate. Here we have contributed and continue to develop new approaches based on the mathematical properties of the stochastic separatrix, or transition state ensemble. The kernel analysis methods we have developed are one excellent example of our development of new theoretical approaches needed to study complex systems. We have also studied how protein architectures transmit such a promoting vibration. In fact, in the protein above, LDH, we have found that the protein is arranged to preferentially transmit heat along the promoting vibration axis. Aside from the fascinating protein engineering questions this raises, it also provides a new experimental tool for investigation of the promoting vibration. Modern spectroscopic techniques allow interrogation of local temperatures in proteins following excitation, and collaborators are using this method to identify promoting vibrations. In other joint work, with our collaborator Prof. Vern Schramm, we asked how could one disrupt the vibrations in an enzyme without changing any of the other factors that control chemistry. The answer is to change the masses of all the atoms to heavy isotopes - the Born-Oppenheimer enzyme. This has led to one of the most convincing joint experimental/theoretical confirmations of the concept of femtosecond motions in a protein helping to control reaction dynamics. Another research area we are studying relates to the quantum nature of chemical reactions in enzymes. There has long been controversy as to whether enzymes are evolutionarily optimized to take advantage of quantum tunneling. In order to study this problem we have developed an approximate quantum TPS using semiclassical mechanics to study quantum effects. We study enzymes from organisms that have appeared at different times in evolutionary history. For example, lactate dehydrogenase from a human and from a bacillus. If the quantum reaction coordinate in both cases is very similar to the classical, then the argument against the evolutionary optimization of tunneling is bolstered. On the other hand if the more evolved enzyme shows a larger deviation between the quantum reaction coordinate and the classical, then there is a strong argument for such evolutionary effects. In our basic theory development we have created a new mixed quantum-semiclassical dynamics methodology. The method is based on corrections to an approximate evolution method (such as semiclassical gaussian propagation) with rigorous quantum theory. The interaction like representation yields a formal expression for the evolution operator: 
We have developed practical methods of application of this formal equation to systems as complex as enzymes and will now be applying it to quantum dynamics in such systems. Finally, a new and exciting area of work in my group is the study of complex multi-protein machines. In particular, we wish to understand the control machinery of cardiac muscle tissue. My collaborator, Dr. Jil Tardiff, studies how mutations in specific components of the thin filament of cardiac muscle cause a devastating set of diseases collectively known as hypertrophic cardiomyopathy (the one that causes young athletes to die suddenly.) While the biophysical and physiologic experiments she performs shed great light on the causes of disease, in order to understand the effect of the causative mutations on a molecular level, we apply computational methods. In order to do this, we have built an atomic model of the thin filament of cardiac muscle tissue shown below. 
This is the first unified model of the entire unit of the thin filament, and was built from many extant crystal structures. It is thermodynamically stable, and simulations have already shown how calcium binding to the thin filament regulates myofibular function, how phosphorylation effects this modulation, and finally how specific mutations change the function. We are developing a coarse grained simulation methodology that allows true physiological timescale simulation of this component of the thin filament. This project represents an exciting application of basic theoretical and computational chemistry to both the function and modulation of cardiac muscle contraction, and to understanding and potentially ameliorating a deadly disease. | |||
Selected Publications | |||
Please see my Research Group Webpage. | |||
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