Kresten Lindorff-Larsen, Professor at the Linderstrøm-Lang Centre for Protein Science in the Department 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 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 naturally 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 protein 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 enjoying 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 alternative civilian service and then worked for a biotech company 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. Cambridge was a hotspot for such research with people such as Chris, Alan Fersht, Jane Clarke, Michele Vendruscolo, Carol Robinson, 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 Linderstrøm-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 tertiary structures in proteins and inventing hydrogen exchange to study protein structure and dynamics,” he reports. “The Linderstrøm-Lang Centre brings together protein scientists with a broad set of interests and skills and is highly collaborative.”
“Our current research falls into two broad themes. In one area, we combine molecular simulations with experiments to study the structure, function, and dynamics of proteins. Many of these projects are collaborative, and I enjoy working closely with experimental groups and developing the techniques needed to integrate experiments and simulations as closely as possible. In this research we work on many different types of systems, including folded, globular proteins, membrane proteins, and highly disordered proteins. Another major theme in the group is to predict and understand the impact of missense variants on protein stability and function,” he conveys. “Here, the goal is to figure out which missense variants cause disease, and what the molecular mechanisms might be. This work is also collaborative, and we work closely with people who perform cell-based and biochemical assays.”
Lindorff-Larsen finds the collaborative nature of science to be one of the most rewarding parts of research. “While the work I am doing is continuously changing, I have always enjoyed trying to bring together different expertise and methods to tackle new types of problems,” he shares. “Over the years we have worked together with many experimental groups combining our methods and ideas to move the field forward. I also very much enjoy learning from and being inspired by the people in the group. A nice thing about biophysics is that many of the problems really require the use of many different methods, so it is often highly collaborative by nature.”
While biophysics is a broad, diverse field moving forward in many directions, in his areas of focus Lindorff-Larsen has been trying to push research forward in two main directions. “First, we are increasingly focusing on the dynamics of complex biomolecular systems and how these dynamics relate to function. Second, we are pushing to move computational biophysics to the proteome scale,” he declares. “One recent example is that we have calculated the effects of all possible missense variants on the stability of all human proteins, substituting each amino acid for all 19 other possibilities at each residue. Another example is our recent work in which we performed molecular simulations of all 28,000 disordered regions from the human proteome.”
One piece of advice he shares for early career biophysicists is not to listen to too much advice. “Or rather, to realize that we each do what we do in different ways, and our paths are varied. That said, there are a few things that are important for me. First, I think research should be fun and creative. Second, I enjoy collaborative science and we will often select projects that enable us to learn new things by working with others. Third, I have personally benefitted a lot from having a good overview of the literature. In a time where many things move very rapidly, I think one can often learn a lot by remembering that biophysics is not a new field, and that we can build on the research, ideas, and results from many others over the years. So, instead of just reading the same papers as everyone else, I recommend also to read outside the most recent big publications,” he advises. On a broader scale, “My main advice would be to find something you enjoy doing, and see whether you can find a way of getting to work on those things.”