Biophysical Society Bulletin | November 2021


Mario Amzel

A hallmark of Mario’s scientific approach was his application of first-principles thinking to a diverse set of biological problems. His lab had a project portfolio as diverse as some departments: mainstay techniques covered thermodynamics, kinetics, struc- tural biology, and computational modeling and dynamics, while biological systems included antibodies, enzymes, redox proteins, structural proteins, ion channels, and transporters. He was as proficient designing constructs to program living cells as he was writing software, even with punch cards, which he kept by his desk to remind his students of the accelerated pace of scientific progress. Despite this breadth of study, Mario always wanted to know the details of what his students were doing. If an algorithm was not working as expected, he would usually show up the next morning with a printed or hand-written piece of paper containing new code to solve the problem. He invariably found the simplest andmost parsimonious solutions. Mario employed a diverse repertoire of structural biology, bio- chemical, and computational methodologies to advance the fields of structural enzymology, membrane transport, and cancer, to name a few. Since his pioneering work elucidating the structure of an antibody, Mario determined the structures of a long list of major proteins and enzymes, including the rat liver F1-ATPase, NAD[P]H:quinone reductase 1 and 2, bovine odorant binding pro- tein, di-copper monooxygenase (PHM), soybean lipoxygenase-1, andMICAL-1monooxygenase. A gifted biophysicist, Mario was as comfortable using X-ray crystallography as he was using quan- tummechanics/molecular mechanics (QM/MM) hybrid simula- tionmethods. His wide-ranging expertise in theory and practice is evidenced by the vast array of systems he studied, such as intermediate redox species in PHM, conformational fluctuations of phosphatidylinositol-3-Kinase (PI3K), actin filament oxidation by MICAL-1monooxygenase, and titin unfolding by applied force. High-impact results that stemmed fromhis versatile approaches tomechanistic enzymology included use of tumor genotyping to determine the molecular mechanisms by which specific cancer- associatedmutations of PI3K led to its activation. Mario’s decades-long collaboration on the function and trans- port mechanismof the Na + /I - symporter included investigations using double-bilayer molecular dynamics (MD) simulations of the transporter in an ionic concentration gradient to investigate residue-ion interactions, ion coordination, putative ion binding pockets, and the effects of ion binding on transporter dynamics through elastic network modeling. Mario had an unparalleled understanding of thermodynamics and how it pertained to protein folding and association, conformational dynamics, and enzymatic activity. He was particularly inspired by the elegance of Jarzynski’s equality, which relates equilibrium free energy differences between two states to the work done when the system is driven repeatedly and irreversibly between the two states. Motivated by this result, he developed a method to compute free-energy differences using non-equilibriumMD simulations. Mario’s underlying passion for thermodynamics

Known as a “scientist’s scientist” and devotedmentor, Mario Amzel (1942– 2021) is remembered by his colleagues and students for Aristotelian walks around the East Baltimore community that he helped reshape while leading the Department of Biophysics and Biophysical Chemistry at the Johns Hopkins University School of Medicine

for 15 years. Having completed his graduate education amidst a military coup in his beloved Argentina, Mario understood the importance of access to education for all and was a strong proponent of diversity through integration. This conviction was evidenced by his unwav- ering support for Baltimore’s disadvantaged youth, aspiring grad- uate students, junior faculty at Hopkins, andmany established scientists around the world. Mario expanded the Department of Biophysics and Biophysical Chemistry by eight faculty positions and led searches to broaden the expertise and backgrounds of department faculty. A devoted faculty mentor, Mario declined a move to a new building to remain near the junior faculty. An impassioned educator, Mario had a separate entrance installed in his office to be more accessible to students and train- ees. Mariomentored by fostering understanding, empowerment, independence, and a passion for knowledge, but most impor- tantly, he genuinely cared for the well-being and success of his mentees. Mario created an inclusive environment characterized by mutual respect, and the lab bonded over frequent discussions fueled by wine and charcuterie. He opened his house for end-of- the-year fireworks, as well as for lab parties and picnics, where he would personally grill delicacies for hours, asado-style, nomatter the weather. As his mentees, we learned the power of reaching out to other mentees and colleagues and always listening to dissenting opinions, and we cherishedMario for providing space for us to grow. Beyond the kindness, care, and friendship he shared with his 33 graduate students, 15 postdoctoral fellows, and countless colleagues, Mariomade invaluable contributions to science. From the first structures of antibodies to the enzymatic mechanisms of ATP synthesis and the structural basis of oncogenic mutations, Mario authoredmore than 220 peer-reviewed publications and was cited over 19,000 times. He was also a Fellow of the Bio- physical Society and the American Association for the Advance- ment of Science. When asked about retirement, Mario’s response never wavered. He couldn’t understand why anyone who loved their job as much as he loved science would want to retire. He planned to continue teaching, mentoring, and pursuing discovery as long as he couldmake a difference.

Mario Amzel

November 2021



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