Steven D. Schwartz
address: Department of Chemistry and Biochemistry
1. Theoretical and computational biochemistry
We study the 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 develop and employ rare event simulation tools such as Transition Path Sampling to overcome these obstacles
and provide unbiased mechanistic information.
We also work on incorporating these insights into methodologies of enzyme design and studies of enzyme evolution.
Recent results include:
● J. Schaffer, I. Zoi, D. Antoniou and S. D. Schwartz,
Optimization of the turnover in artificial enzymes via directed evolution results in
the coupling of protein dynamics to chemistry, JACS 141, 10431 (2019)
● R. Harijan, I. Zoi, D. Antoniou, S.D. Schwartz and V.L. Schramm:
Inverse enzyme isotope effects in human purine nucleoside phosphorylase with
heavy asparagine label, PNAS 115, 2609 (2018)
● V. L. Schramm and S.D. Schwartz: Promoting vibrations and the function of enzymes.
Emerging theoretical and experimental convergence, Biochemistry 57, 3299 (2018)
● I. Zoi, D. Antoniou and S.D.Schwartz:
Electric fields and fast protein dynamics in enzymes, J. Phys. Chem. Lett. 8, 6165 (2018)
● I. Zoi, D. Antoniou and S.D. Schwartz: Incorporating fast protein dynamics into enzyme design:
a proposed mutant aromatic amine dehydrogenase, J. Phys. Chem. B 121, 7290 (2017)
● R. Harijan, I. Zoi, D. Antoniou, S.D. Schwartz and V.L. Schramm: Catalytic-site design for inverse
heavy-enzyme isotope effects in human PNP, PNAS 114, 6456 (2017)
● 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)
2. Mechanisms of genetic cardiac disease
We perform 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, J. Tardiff and S.D. Schwartz:
The mechanism of cardiac tropomyosin transitions on filamentous actin as revealed by
all atom steered molecular dynamics simulations, J. Phys. Chem. Lett . 9, 3301 (2018)
● M. McConnell, M. Williams, M. Lynn, B. Schwartz, S.D. Schwartz and J. Tardiff:
Clinically divergent mutation effects on the structure and function of the
human cardiac tropomyosin overlap, Biochemistry 56, 3403 (2017)
● M. Williams, S. Lehman, J. Tardiff and S.D. Schwartz, Atomic resolution probe for allostery In the
regulatory thin filament, PNAS 113, 3257 (2016)
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.
● E. Munusamy, C. Luft, J. Pemberton and S.D. Schwartz: Unraveling the differential aggregation of anionic
and nonionic monorhamnolipids at air-water and oil-water interfaces:
a classical molecular dynamics simulation study, J.Phys. Chem. B 122, 6403 (2018)
● C. Luft, E. Munusamy, J. Pemberton and S.D. Schwartz: Molecular dynamics simulation of the oil
sequestration properties of a nonionic rhamnolipid, J.Phys. Chem. B 122, 3944 (2018)
● E. Munusamy, C. Luft, J. Pemberton and S.D. Schwartz: Structural properties of nonionic
monorhamnolipid aggregates in water studied by classical molecular dynamics simulations,
J. Phys. Chem. B 121, 5781 (2017)