Biophysical Society Bulletin | January 2021

Biophysicist in Profile

Alan Grossfield Areas of Research Using simulations to understand how physics determines biological function

Institution University of Rochester Medical Center


Alan Grossfield grew up interested in math and science, with parents who worked in quantitative fields, as a math teacher and a structural engineer. “When I was about five or six years old, I heard my parents mention pi,” he shares. “To deflect my disappointment that we weren’t discussing dessert, my dad got a bunch of cans out of the cupboard, along with a piece of string and a ruler, and we measured pi. I remember the shock and glee I felt when the same number came up, over and over.”

Alan Grossfield

As a high school student, Alan Grossfield started asking big questions in his advanced biology class. “We were studying how ribosomes worked, and I got really frustrated with the teacher. He was explaining that the tRNA did this, then the ri- bosome does that, and then the protein chain gets longer, and it kept sounding like the ribosome knew what it was trying to accomplish. I kept asking how it did it, since the molecules don’t have intent, and I got mad the teacher didn’t know,” he explains. “Of course, it wasn’t his fault — the first ribosome crystal structure wasn’t published until eight years later — but I came away convinced that I wanted to understand why molecules do stuff. I’ve never gotten past that — realizing that a bunch of molecules that only communicate by direct collisions manage to create function across nine orders of magnitude in length scale still blows my mind.” He started at Cornell University in 1990 as a biology major. “I was already interested in biophysics, but I didn’t know the word,” he says. “I was very lucky that my assigned freshman advisor was Jerry Feigenson . Although that relationship is only official for freshmen, I went back to him for advice in the middle of my sophomore year. I was getting frustrated with my classes; I wasn’t learning what I wanted to know, and I was sick of all the memorizing I had to do in my bio classes. Jerry listened, and after a while he suggested I’d be happier switching to a physics major.” Grossfield did change majors at the end of his sophomore year and finished his degree in physics with a concentration in biology in 1994. He then entered a graduate program at Johns Hopkins University which was then called the Intercampus Program in Molecular Biophysics. He was the first student in the lab of Thomas Woolf , using molecular dynamics simulations to study membrane-protein interactions, focusing mostly on the interactions between analogs of tryptophan side chains and the membrane-water interface. In the late 1990s, Daniel Zuckerman , now a professor at Ore- gon Health & Science University, joined Tom Woolf’s group at

Johns Hopkins as a postdoc late in Grossfield’s time there as a grad student. “Although nominally I was senior to Alan, in fact he was a mentor to me in terms of learning structural biology, membrane biophysics, and good computational practices,” Zuckerman shares. “Alan is very astute in his physical think- ing and his ability to spot problems in data, which are really critical skills in our field.” Following the completion of his PhD program in 2000, he started a postdoctoral fellowship at Washington University School of Medicine in St. Louis with Jay Ponder in the Depart- ment of Biochemistry and Biophysics. He had been struggling with computational limitations on the quality of statistical sampling, so he decided to change lanes to do modeling where statistical sampling was not a major problem. “I went to Jay’s lab to work on some protein structure prediction work involving potential energy smoothing, but once there I switched gears to study the solvation thermodynamics of simple ions using the AMOEBA polarizable force field, which was being developed at that time by Jay and another postdoc in the lab, Pengyu Ren ,” he explains. “It was a very exciting time to be a computationalist at the med school. From Jay, I learned a huge amount about simulation methods, as well as how to design code to be clear and maintainable. The Center for Computational Biology had hired several outstanding new faculty members, including Rohit Pappu , Nathan Baker , and David Sept . I knew Rohit from my grad school days — he had a lot to do with my choosing to go work for Jay — but I found the volume and diversity of work going on in all of their labs inspiring, and watching them navigate the new professor experience informed my choices when I got my own lab years later.” In 2004, he moved back to Yorktown, New York, where he grew up and began a second postdoc at the IBM TJ Watson Research Center. An informal mentor of Grossfield’s since graduate school, Scott Feller , had been collaborating there with Michael Pitman on simulations of lipid membranes, and

January 2021



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