In this communication, I will showcase some of the research I conducted after leaving ICIQ, switching from the simulation of nonbiological catalysts to biological ones (i.e., enzymes).
I will mainly focus on the work I carried out during my current position in Pavia, whereby I was able to model and justify the peculiar reactivity of the (homodimeric) mitochondrial chaperone Trap1 (Figure 1; right). This molecular machine—whose activity and/or expression levels are notably altered in several cancers—oversees the correct folding of bound “client” proteins, a feat which it achieves through extensive conformational rearrangement. Kickstarting this rearrangement are two strictly sequential ATP hydrolyses, which can only occur once the chaperone adopts a distinctive asymmetric “closed” state (Figure 1; left): intriguingly, the ATP molecule bound to the buckled protomer Buc is cleaved first (and, even so, sluggishly); conversely, the straight protomer Str remains catalytically inert until the first hydrolysis has triggered its own buckling.
Using a previously tested recipe, classical molecular dynamics (MD) proved that, in Str, nucleophilic water WatNuc is more frequently sequestered, via tighter hydrogen bonds, by a (conserved) tyrosine and its vicinal water WatTyr: “reactive poses” (Figure 1; left) are thus more frequent in Buc. Hybrid semiempirical quantum-classical (QM/MM) MD with umbrella sampling, benchmarked with density functional theory, thence confirmed that looser WatNuc sequestration is enough to lower the free energy required for hydrolysis.
If time allows, I will conclude with a summary of our current work on SARS-CoV-2 proteins.
Figure 1. (Left) Overview of zebrafish Trap1 (zTrap) with its protomers in the asymmetric “closed” state. (Right) One of zTrap’s active sites just prior to ATP hydrolysis (green sphere: Mg2+).
 Sánchez-Martín, C.; Serapian, S. A.; Colombo, G.; Rasola, A., Front. Oncol. 2020, 10, 1177.
 Elnatan, D.; Betegon, M.; Liu, Y.; Ramelot, T.; Kennedy, M. A.; Agard, D. A., eLife 2017, 6, e25235.
 Serapian, S. A.; van der Kamp, M. W., ACS Catal. 2019, 9, 2381.
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