Biophysicist in Profile

SANDRASEGARAM GNANAKARAN

Sandrasegaram Gnanakaran, known to his friends and colleagues as “Gnana,” learned independence early. When only eleven years of age, he left his family and the rural Sri Lanka town where he grew up to attend a prestigious school in the capital city of Colombo. With his father serving as a senior official in the Ministry of Education, Gnana grew up understanding the value of a good education. Science, however, was not the field he envisioned himself pursuing. “Had I remained in my country of birth,” he says, “I would probably have pursued a professional career like engineering or medicine.” Staying close to home was no longer an option when Sri Lanka’s violent civil war broke out when Gnana was in high school in Colombo. During the riots in July 1983, one of his classmates was killed, and Gnana nearly lost his life as well. The family home was burned, and Gnana spent several days in hiding before ending up in a refugee camp. It was not long until his family sent him to the US to continue his education in a more stable environment.

After moving to the US, Gnana enrolled as an undergraduate at Virginia Commonwealth University, and it was during his time there that he first took an interest in scientific research. In particular, an independent research course under the direction of Sarah Rutan spurred his decision to pursue graduate studies in computer science and chemistry. Gnana enrolled in a PhD program in physical chemistry at the University of Pennsylvania, where he studied energy transfer and relaxation of vibrationally excited molecules in different solvents under the mentorship of Robin Hochstrasser. During his time in Hochstrasser’s lab studying protein dynamics using IR spectroscopy, Gnana says, “I became interested in research problems at the interface of biological and physical sciences.” Working with Hochstrasser taught Gnana the value of tackling a scientific problem from many different angles. Gnana has carried this multipronged approach with him throughout his scientific career.

Gnana continued in Hochstrasser’s lab as a postdoc, during which time, he says, “I was involved in the theoretical interpretation of new 2D-IR spectroscopy that was started around that time in his group. I used molecular dynamics simulations to deduce conformations of peptides in conjunction with 2DIR.” This work strengthened Gnana’s interest in biophysics, and specifically sparked his curiosity about protein folding. He wanted to learn more about computational approaches to study protein folding, so he was excited to hear that Angel Garcia was looking for a postdoc. Gnana approached Garcia at the Biophysical Society Annual Meeting, and soon began work in Garcia’s group at the Los Alamos National Labs (LANL).

Coming from an experimental lab, Gnana had much to learn about the theoretical approaches to studying protein dynamics, folding, and misfolding. Thankfully, Garcia was an excellent mentor. “He had a vision of how computational approaches can be used to solve challenging biophysical problems,” Gnana explains.

After completing his postdoc with Garcia, Gnana stayed on in the theoretical biology and biophysics group at LANL as a staff scientist. One of the great benefits of working at LANL has been the close proximity of talented researchers in a variety of fields. “As I have started studying more biophysical problems,” Gnana says, “I realize that no single approach is enough to solve a problem, and many different approaches need to be implemented together.” With access to this impressive pool of researchers, an interdisciplinary approach has become an important feature of his current research program. One of his frequent collaborators at LANL is Byron Goldstein. The pair has recently worked together to build detailed models of cell signaling cascades. These models can be problematic because they contain a large number of parameters that need to be evaluated in order for the models to have predictive value. Goldstein explains, “Gnana and I have collaborated to try to bring structural biology to bear on these models. A first goal of ours is to improve the estimates of equilibrium and rate constants that characterize intramolecular reactions and intramolecular interactions that occur on surfaces, parameters that are difficult to determine experimentally.” They have already shared some success on this project, in estimating the intramolecular equilibrium constants from measured solution binding constants for the binding of the adaptor Grb2 through its two SH3 domains to the five polyproline binding sites on the nucleotide exchange factor son-of-sevenless 1. Gnana does not accept superficial explanations, demanding to get to the heart of the problem, but he does it in a gentle way.”

Gnana is currently leading a project at LANL to address efflux pump mediated drug resistance –the dominant drug resistance mechanism in gramnegative bacteria. “At present, we rely heavily on antibiotics for the treatment of bacterial infections encountered in public health and bio-threat scenarios,” he explains, “however, the rapid emergence of antibiotic resistance poses a major hurdle in the treatment of infections.” Gnana and his team are working to develop an experimentally-driven mathematical framework that will integrate structural, genetic, and cellular processes in order to understand how multi-drug resistance efflux pumps are able to resist so many antibiotics.

Gnana’s group has also been instrumental in establishing theoretical capabilities to overcome challenges related to cost-effective biofuels. “Biophysical questions concerning the enzymatic degradation of cellulose are what really got me started in this field,” Gnana explains, “We understand somewhat how enzymes catalyze reactions in an aqueous environment. However, in the case of cellulosic conversion of glucose to ethanol, we needed to know how three kinds of enzymes work together in synergy to break down crystalline cellulose to glucose.” The group at LANL has been working with the Great Lakes Bioenergy Center to find which properties determine efficient catalysis of an enzyme on native and non-native cellulose surfaces. They have also developed mathematical models to identify proper mixture of these enzymes that effectively degrade cellulose.

When he is not in the lab, Gnana is often still thinking about biophysics, as one of the organizers of the q-bio Conference (www.q-bio.org), which he calls “a forward-looking conference on quantitative biology.” Gnana also looks forward to going home each day, where he enjoys spending time with his wife and two young children. He has even begun to share his love of sports with his daughter. Says Goldstein, “When his first child was a year old, Gnana began to watch Sunday football (American) with her on television. He introduced her to baseball as well, taking her to see the Albuquerque Isotopes play. Now three, she can talk baseball. I am sure Gnana will give his son the same broad educational experience.” For those just starting out in biophysics, Gnana has this advice, “Have a broad perspective on biophysics. As a biophysicist you often encounter setbacks or failures…What defines success is how one deals with failures and turns them into advances.”

For those just starting out in biophysics, Gnana has this advice, “Have a broad perspective on biophysics. As a biophysicist you often encounter setbacks or failures…What defines success is how one deals with failures and turns them into advances.”

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