Biophysical Society Bulletin | May 2024

Biophysicist in Profile

Kresten Lindorff-Larsen Area of Research Computational protein biophysics

Institution University of Copenhagen

At-a-Glance

Kresten Lindorff-Larsen , Professor at the Linderstrøm-Lang Centre for Protein Science in the De partment of Biology, University of Copenhagen, studied biochemistry, leading him to the world of protein science and biophysics. After completing his PhD at the University of Cambridge, and a short postdoc, he took a faculty position at the University of Copenhagen. His lab combines molecular simulations with experiments to study the structure, function, and dynamics of proteins and works to understand the impact of missense variants on protein stability and function.

Kresten Lindorff-Larsen

Kresten Lindorff-Larsen was born in Denmark to a mother who was a surgeon and a father who worked as a dancer, actor, and director. His maternal grandmother was a successful actress and singer who also earned a university degree at age 60, and his maternal grandfather was a musician and composer. “All of them had broad interests, and I think I have inherited this,” he shares. “And while I do not have any of the musical creativity of the rest of the family, I think that I have been able to use creativity in the way we do science.” Having a fascination with the world around him, he was nat urally drawn to science and math. In high school he focused on biology, chemistry, and math. “While I seriously considered studying medicine, I ended up studying biochemistry at the University of Copenhagen, and this led me to the field of pro tein science and biophysics. I was already interested in more chemical and quantitative aspects of biochemistry back then, and so supplemented with additional coursework in math and physical chemistry,” he recalls. “I performed research for both my bachelor’s and master’s degrees at the historical Carlsberg Laboratory. The Carlsberg Laboratory is located next to the Carlsberg brewery and is a research institute that historically has been very focused on basic science. A lot of important protein science and chemistry has been done there over the years, and it had a wonderful atmosphere. I remember enjoy ing going to the library to find all the issues of a wide range of journals back to their beginnings.” After obtaining his master’s degree, he completed his alter native civilian service and then worked for a biotech com pany before pursuing a PhD in the lab of Chris Dobson at the University of Cambridge. “I was trained as an experimental biochemist and went to work for Chris with the intention to do experimental biophysics. I was fascinated by biophysics in general and the process of protein folding in particular. Cam bridge was a hotspot for such research with people such as Chris, Alan Fersht , Jane Clarke , Michele Vendruscolo , Carol Rob inson , and many others, and of course a lot of amazing young people in all these groups. Chris had just moved from Oxford

to Cambridge, and the wet lab was pretty much non-existent when I arrived,” he explains. “Before going to Cambridge, I had done a bit of programming and quantitative analyses, and so ended up talking to Chris and Michele about some ideas I had. And very much by chance I therefore ended up switching from wet lab experiments to computational experiments. Both in Cambridge and later I have, however, tried to combine my interest in experimental protein science with computational methods.” After completing his PhD, he moved quickly to a faculty posi- tion. “I was fortunate to be offered an assistant professor position at the University of Copenhagen almost straight out of my PhD, so I only did about six months of postdoc in the lab of Flemming Poulsen before starting my own research group,” Lindorff-Larsen says. After two years as an assistant professor, Lindorff-Larsen left Copenhagen to join D. E. Shaw Research in New York. There he joined a diverse group of people working on developing software, hardware, and algorithms for molecular dynamics simulations and applying these to problems in biology and biophysics. “This was an exciting time as we were beginning to use a specialized computer—called Anton—to perform long molecular dynamics simulations of protein dynamics and folding,” he recounts. “Together with my colleagues, I was able to use my background in, for example, NMR [nuclear magnetic resonance] spectroscopy to improve force fields, and then apply these to study the process of protein folding.” After four years in New York, Lindorff-Larsen moved back to Copenhagen where he is currently a professor at the Linder strøm-Lang Centre for Protein Science in the Department of Biology at the University of Copenhagen. “Our center is named after the Danish protein chemist Kaj Linderstrøm-Lang , who was head of the Carlsberg Laboratory and who is famous for, among other things, naming primary, secondary, and ter tiary structures in proteins and inventing hydrogen exchange to study protein structure and dynamics,” he reports. “The

May 2024

4

THE NEWSLETTER OF THE BIOPHYSICAL SOCIETY