Mapping the Kinetic Landscape of Biomolecular Processes
Understanding biomolecular processes at the molecular level, which is often the goal of biophysical studies, requires bridging many time- and length scales. While computer simulations can now routinely capture the motion of most biomolecules for microseconds, biological processes typically occur on a millisecond or longer time scales. Moreover, capturing a millisecond process for a single molecule represents just one example of billions of molecules that make up the ensemble of molecules in a test tube or cell. For each molecule or each repeated process, there will be slight variations. Only by averaging all of these, formally with statistical mechanics, can chemists recover the consistent properties they measure in experiments and thereby connect a molecular-level understanding with a bimolecular process.
Professor Swanson and her research group are developing multiscale kinetic modeling and simulation methods to take on this challenge by probing not only the structure and dynamics of specific microscopic transitions but also the variation in how proteins move through those transitions (kinetic pathways). Collectively these competing pathways, each contributing different amounts to the final outcome (e.g., ion transport) make up a kinetic network, although it is perhaps better thought of as a kinetic landscape with biomolecules flowing through it according to the relative ease (free energy) of each transition. Single-molecule experiments also shed new light on these kinetic variations as they trace out how biomolecules transition through such kinetic landscapes, one molecule at a time.
The Swanson Group also specializes in bridging quantum and classical regimes (size scales) to describe reactive processes while using various approaches to free energy sampling in addition to kinetic modeling to bridge time scales. The ultimate goal: connecting atomistic descriptions with macroscopic properties and biological relevance.
Effective Diagnostics for Buruli Ulcers
One topical focus in the group is biophysics. Recently, their findings shed new light on the ways in which amphipathic pathogen molecules navigate host systems. The group is part of an ongoing project exploring the mechanism that allows the mycolactone toxin to cause the ruthless skin disease, Buruli ulcer, which is in the same family as leprosy. The ulcers are chronic, debilitating, and caused by a single molecule that looks completely innocuous, like cholesterol or lipid. This toxin leads to tissue necrosis, evades the immune system, and blocks pain, making it incredibly difficult to detect before it’s already caused a significant amount of damage.
Developing effective diagnostics that target the toxin has been unsuccessful to date. Simulations from the Swanson Group have revealed the likely cause is a constant association with and trafficking via host membranes. It is now known that the toxin travels from outside of a host cell through the plasma membrane to the endoplasmic reticulum (ER), where it associates with the sec61 translocon, blocking the uptake of half of the cell’s membrane proteins. This causes a wide array of downstream consequences.
One key question is how does the toxin’s localization enable its pathogenicity? Swanson’s group calculated free energy profiles for the strength of association with different membranes to see if the toxin is trafficked simply via preferential interactions with different lipids. They were also able to observe through their all-atom simulations that although coarse-grained simulations gave the correct free energy of membrane association, they failed to capture both the mechanism of permeation and the role that water played during the permeation. Their quantum to classical and kinetic modeling simulations continue to map the mechanism of this toxic molecule into a clear narrative that will lead to more effective diagnostics.
Lipid Droplets & Metabolic Disease
Professor Swanson is also leading her group’s research to understand how proteins preferentially interact with lipid droplets to enable and control their lifecycle and essential process in metabolism. Dysregulation of these protein interactions results in metabolic dysfunction and disease. Lipid droplets are energy storage organelles where the body stores fatty acids and triglycerides, which are our densest form of fuel.
Enzymes synthesize fatty acids in the ER membrane where proteins facilitate their transfer into lipid droplets. A unique property of these organelles is that they are surrounded by a phospholipid monolayer rather than a bilayer. The Swanson Group is using simulations to identify the mechanisms by which proteins preferentially seek out lipid droplets.
What they have found so far is surprising: first, there is more water in the hydrophobic core than previously believed (glycerol groups are polar); and second, the triglycerides actually intercalate with the phospholipids in the monolayer surface creating more chemically unique packing defects that are not present in typical bilayers. They are currently probing how proteins interact with these new surface properties, anticipating they will have significant consequences for lipid droplet regulation.
Department Collaboration
Swanson’s group has just teamed up with Professor Andrew Robert’s group in a collaborative research project concerning the synthesis of biologically active lasso peptides as potential therapeutics with improved metabolic stability. The Swanson Group will provide molecular dynamics simulation data to assist the Roberts laboratory with the design and understanding of chemical systems for spontaneous lasso peptide folding.
Diversity, Equity, and Inclusion in STEM: A Call for Life Balance for All
Professor Swanson optimistically acknowledges that “we’re on our way” when it comes to creating work environments that make it easier to retain women faculty. Although she has felt respected here at the U’s Department of Chemistry “from day one,” she acknowledges that there are still men in her field, and even women, who make inappropriate comments and fail to recognize the built-in bias of many departments and divisions across the country. Although there’s still a lot of room to grow, she optimistically affirms that Utah is closer to creating life balance than other institutions, including her former University of Chicago.
More than anything, Professor Swanson feels an urgent need to bring more life balance to the world of academics for both women and men. She sees both male and female colleagues “drowning” and “exhausted” from carrying childcare or other life responsibilities, in addition to the massive workload expected to stay competitive in their research and teaching. Too often she feels in academics that she has to choose between being successful (tenure and beyond) and having a healthy life in addition to work. “Most women turn away from pursuing academics for this reason alone,” she says. “It’s sad to me. We should not have to choose between being good parents, or whatever other aspect of life someone holds precious, and getting tenure or being respected by our colleagues.”
She, like many of her colleagues and students, would like to see a third option: the space to thrive in both work and life. What would that look like? It seems highly reasonable that with all the brilliant minds in STEM, we could imagine solutions that would give academics more bandwidth to contribute professionally and thrive personally.
Hopefully her recent arrival and influence at the University of Utah Department of Chemistry, which she states “is a breath of fresh air” after her time at Chicago, will contribute to the ever-expanding diverse and inclusive culture here at the department.
Lydia Fries was awarded a Goldwater Scholarship for 2020-21. As a junior in chemistry, Lydia intends to obtain a Ph.D. in either organic chemistry or electrochemistry. She has done research in both Matt Sigman and Shelley Minteer’s groups, and Lydia is an author of two papers with both professors. She has worked on a variety of projects involving electrochemistry, palladium catalysis, and computationally focused projects. As an undergraduate, she enrolls in many graduate-level courses and is a Teaching Assistant for Organic Spectroscopy I. Lydia has been accepted to an REU program this summer and hopes that the current pandemic will have subsided by the time her program begins in mid-May.
With encouragement from high school teachers, Lydia followed her passion and her strong aptitude for STEM subjects and ignored the warnings from her broader community that she shouldn’t pursue such an expensive and “useless” degree. She followed her heart and her brain to the University of Utah, where she landed in the ACCESS program and was immediately surrounded by many intelligent and motivated women.
The American Chemical Society, the world’s largest scientific society, has awarded the 13th Irving S. Sigal Postdoctoral Fellowship (2020-2022) to Dr. Olja Simoska.
Olja completed her doctoral studies in December 2019 under the supervision of Prof. Keith J. Stevenson at the University of Texas at Austin. Her doctoral dissertation is titled “Real-time Monitoring of the Dynamic Metabolism and Responses of Pathogenic Bacteria using Electroanalytical Methods.” The electrochemical results from her doctoral research provide a strong quantitative basis for understanding microbial infections and virulence mechanisms in very complex biological systems. She has very impressive academic accomplishments, awards/honors, and publications/presentations lists.
For her Irving S. Sigal Postdoctoral Fellowship, Olja’s research will focus on methodically exploring genetic engineering approaches to improve extracellular electron transfer and performance of microbial fuel cells. Her postdoctoral research will be under the supervision of Prof. Shelley D. Minteer.