Steven D. Schwartz
address: Department of Chemistry and Biochemistry
1. Theoretical and computational biochemistry
We work on identifying computationally atomic details of enzymatic catalysis.
The microscopic mechanism of enzyme catalysis remains a hotly debated topic.
We have proposed that in certain enzymes, motions in the body of the protein
are an integral part of the chemical mechanism.
This was controversial because these motions are much faster than the
turnover rate, but work by us and other groups have verified this effect.
There are 2 practical difficulties in computer simulations of enzymes:
the accessible simulation times are much shorter than biologically important timescales,
and the enzymatic reaction coordinate is unknown.
We use tools like Transition Path Sampling that can overcome these obstacles
and can provide unbiased estimates of atomic details of the mechanism.
Also, we work on incorporating these insights into methodologies of enzyme design.
Recent results include:
● M. Dzierlenga and S.D. Schwartz: Targeting a rate-promoting vibration with an allosteric mediator
in LDH, J. Phys. Chem. Lett. 7, 2591 (2016)
● X. Pan and S.D. Schwartz, Conformational heterogeneity in the Michaelis complex of LDH:
an analysis of vibrational spectroscopy using Markov and hidden Markov modles, J.Phys.Chem. B 120, 6612 (2016)
● I. Zoi, D. Antoniou, V.L. Schramm, S.D. Schwartz et al., Modulating enzyme catalysis through
mutations designed to alter rapid protein dynamics, JACS 138, 3403 (2016)
● M. Varga and S.D. Schwartz, Enzymatic kinetic isotope effects from first principles path sampling
calculations, J. Chem. Th. Comp. 12, 2047 (2016)
● M. Dzierlenga and S.D. Schwartz, Another look at the mechanisms of hydride transfer enzymes
with quantum and classical transition path sampling, J. Phys. Chem. Lett. 6, 1177 (2015)
● X. Pan and S.D. Schwartz, Free energy surface of the Michaelis complex of LDH: a network analysis
of microsecond simulations, J. Phys. Chem. B 119, 5430 (2015)
● M. Dametto, D. Antoniou and S.D. Schwartz, Barrier crossing in DHFR does not involve
a rate-promoting vibration, Mol. Phys. 110, 531 (2012)
● S.D. Schwartz and V. Schramm, Enzymatic transition states and dynamic motion in barrier crossing,
Nature Chem. Biol. 5, 551 (2009)
2. Mechanisms of genetic cardiac disease
We work on computational studies of point mutations in cardiac thin filament. Calcium binding and dissociation
within the cardiac thin filament is a fundamental regulator of normal contraction and relaxation.
Mutations that disrupt this allosterically mediated process have long been implicated in cardiomyopathy,
but atomic details of the mechanism remain elusive, preventing the design of new targeted therapies.
¶ We built the first computer model of the thin filament of cardiac muscle and our simulations pinpointed how
mutations in one protein of a complex indirectly affect a second protein via structural and dynamic changes
in a third protein,resulting in a pathogenic change in thin filament function.
This atom-level insight is potentially highly actionable in drug design.
● M. Williams, S. Lehman, J. Tardiff and S.D. Schwartz, Atomic resolution probe for allostery In the
regulatory thin filament, PNAS 113, 3257 (2016)
¶ Our full atomistic model consists of 5 million atoms, which requires a substantial time in a computer simulation.
We developed a coarse-grained model (where each amino acid is replaced by a 2-site block)
whose dynamics is similar to the full atomistic simulation, which alllows for much longer simulations.
● J. Zhang, M. Williams, J. Tardiff and S.D. Schwartz, A coarse-grained model to study calcium activation
of the cardiac thin filament, submitted for publication
3. Micelle formation
Development of novel surfactants is a topic of urgent studies because currently available surfactants have
deleterious environmental side-effects.
We study the formation and dynamics of micelles created from ramnolipids.