(7i) Enhanced Molecular Simulations for Applications in Protein Stabilization, Crystallization, and Structural Determination

Research Interests:

Molecular modeling and simulation can provide researchers with a more detailed understanding of the interactions that underlie important biological and chemical processes. With ever-advancing computer power, researchers can now simulate the molecular-level interactions of proteins, DNA, large polymers, and other organic macromolecules on experimentally relevant timescales. One of the major shortcomings of standard molecular simulations techniques is that they sample molecular conformations that are near local free energy minima. Thus transitions between various states of a system and the barriers associated with those states are rarely visited during a simulation. To overcome these limitations, several enhanced sampling techniques have been developed that allow a researcher to exhaustively sample states of the system and escape local free energy minima. Some of the rarely visited states are often crucial to completely understand thermophysical and transport properties, and such information can not only help us to understand chemical phenomena but also to predict the behavior of chemical systems in silico. I an expert in the application of enhanced and non-equilibrium sampling methods that allow us to answer pertinent scientific questions.

Successful Proposals: Alexander von Humboldt Postdoctoral Fellow. Assisted in writing and gathering preliminary results for NSF and XSEDE/Teragrid applications.

Postdoctoral Project: Enhanced Molecular Simulation and Thermodynamic Characterization of Protein Mutations for Improved Crystallization by Surface Entropy Reduction

Externally funded through the Alexander von Humboldt Foundation. Under the supervision of Prof. Bert de Groot at the Max Planck Institute for Biophysical Chemistry. Göttingen, Germany.

PhD Dissertation: Developing a Simulation Framework for Modeling Biomolecules in Ionic Liquids

Under the supervision of Prof. Jim Pfaendtner at the University of Washington. Seattle, WA.

Research Experience:

The focus of my research has been the computational modeling of protein and ionic liquid systems. As such, I have become an expert in the field of molecular dynamics simulations with an emphasis on enhanced sampling methods that allow us to characterize the thermodynamics of rare events. Specifically, I employ metadynamics and alchemical mutations to determine the relative free energies of multiple states of biomolecular systems and rates of transitions between states as in protein unfolding and ligand unbinding. When I initiate a simulation study, I always look to better explain the molecular interactions that drive experimental results or to predict results of future experiments. Other times, experimental collaborators request my assistance in performing molecular simulations to determine the feasibility of a hypothesis. As such, I have worked closely with several collaborators and even collected experimental data myself. Consequently, I have experience in performing simulations that are relevant to IR, Raman, and SFG spectroscopy as well as microcalorimetry, reaction kinetics, AFM, electron microscopy, XPS, SAXS, and SANS. Therefore, I am confident that I can design and implement simulations that (a) answer important questions about biological and chemical phenomena, (b) support the development of hypothesis in collaboration with other scientists, and (c) efficiently and quickly predict the behavior of biomolecular and organic systems when no experimental data is yet available.

Teaching Interests:

During my time as a PhD student, I had the privilege of training several undergraduate, masters, and fellow young PhD students in the fundamentals of molecular simulation. I find teaching and training of students to be one of the most rewarding parts of my academic career. As a TA, I had the opportunity to teach both core chemical engineering courses such as unit operations, mass transport, and separations as well as electives such as introductory courses to molecular and nanoscale principles. During these courses I gained experience in developing lectures and in the hands-on training of students for the operation of scientific equipment. As a professor, I would feel comfortable in teaching any core chemical engineering course, and I would like to develop a course on molecular simulation to help students better understand the fundamental physics that underlie the thermophysical phenomena we observe as scientists and engineers.

Future Direction:

As faculty, I would like to move my research forward in three distinct fields:

First, I would like to expand my work on thermostabilizing and entropy-reducing protein mutations to include alchemical thermodynamic calculations on mutations that affect the stability of proteins in the presence of chemical denaturants and of enzymes in confinement. With such simulations, we can design proteins that better tolerate a wide range of conditions. The engineered proteins are industrially relevant for a wide variety of applications where enzymes are subjected to stress as in biomass processing, food production, and long-term therapeutic protein storage.

Second, I would like to study peptides that precipitate inorganic nanoparticles. Our previous work indicates that coarse-grained metadynamics simulations can give us a general idea of the shapes of nanostructures formed by a core of small charged peptide with only 1-2 days of simulation time. In nature, many organisms use proteins to transform simple soluable molecules into complex inorganic structures such as diatom exostructures, mollusk shells, and vertebrate bones. Using natural proteins as a starting point, we can run a campaign of simulations to screen thousands of potential nanostructure-forming mutant peptides per year. This work offers the possibility to make well-defined inorganic nanostructures at mild conditions for applications such as catalyst supports or drug delivery.

Third, I would like to develop a protocol for accurately predicting the properties of mixtures of ionic liquids using polarizable force fields. Ionic liquids are liquid organic salts that have many unique properties making them interesting for industrial applications such as biomass processing, batteries, and carbon dioxide capture. Our previous work on ionic liquids has demonstrated that the thermophysical properties of many pure ionic liquids can be predicted using molecular simulation with a generalized non-polarizable force field. We can improve our results by using established polarizable force fields, and we can begin to model mixtures of multiple ionic liquids. With the right computational tools, we can develop highly-tuned ionic liquid recipes to fit the properties required for a wide range of applications.

Selected Publications:

V.W. Jaeger and J. Pfaendtner. Structure, Dynamics, and Activity of Xylanase Solvated in Binary Mixtures of Ionic Liquid and Water. ACS Chemical Biology. 2013. 8 (6), 1179-1186.

V. Jaeger, P.R. Burney, and J. Pfaendtner. Comparison of Three Ionic Liquid-Tolerant Cellulases by Molecular Dynamics. Biophysical Journal. 2015. 108 (4), 880 â?? 892.

J.E. Baio, A. Zane, V. Jaeger, A.M. Roehrich, H. Lutz, J. Pfaendtner, G.P. Drobny, and T. Weidner. Diatom Mimics: Directing the Formation of Biosilica Nanoparticles by Controlled Folding of Lysine-Leucine Peptides. Journal of the American Chemical Society. 2014. 136 (43), 15134-15137.

K.G. Sprenger, V.W. Jaeger, and J. Pfaendtner. The General AMBER Force Field (GAFF) Can Accurately Predict Thermodynamic and Transport Properties of Many Ionic Liquids. The Journal of Physical Chemistry B. 2015. 119 (18), 5882-5895.

V. Jaeger, W. Wilson, and V.R. Subramanian, Photodegradation of Methyl Orange and 2,3-Butanedione on Titanium-Dioxide Nanotube Arrays Efficiently Synthesized on Titanium Coils. Applied Catalysis B: Environmental. 2011. 110, 6-13.