Biophysical Society Thematic Meeting | Hamburg 2022

Biophysics at the Dawn of Exascale Computers

Poster Abstracts

32-POS Board 32 TOWARDS UNDERSTANDING THE FUNCTIONAL DYNAMICS OF ACYL CARRIER PROTEIN MEDIATED SUBSTRATE TRANSPORT IN THE FUNGAL FATTY ACID SYNTHASE Florian Leidner 1 ; Helmut Grubmüller 1 ; 1 Max-Planck Institute of Multidisciplinary Sciences, Theoretical and Computational Biophysics, Göttingen, Germany Fatty acid biosynthesis is a central pillar of metabolism providing essential molecules for energy storage, signal transduction and cell wall integrity. In eukaryotes the multiple enzymes required for the synthesis of fatty acids are combined in large multifunctional enzyme complexes. The nascent fatty acid is shuttled between enzymatic domains by an integral acyl carrier protein (ACP). This transfer process is assumed to be stochastic, regulated primarily by steric occlusion and the spatial organization of active sites within the multienzyme complex. In addition, recent studies have identified a regulatory subunit, which can alter the enzymatic activity of the fungal fatty acid synthase (FAS). Cryo-electron microscopy shows that this change in activity is concomitant with a conformations rearrangement of the ACP domain. Yet it is unclear how the presence of this subunit alters the dynamics of substrate transport. Here we show the effect of the regulatory subunit on the dynamics of ACP following initiation of fatty acid biosynthesis. Advances in high performance computing have made it possible to simulate even large systems such as the yeast FAS (approx. 200.000 heavy atoms) at biologically relevant timescales. We modeled the 2.5 MD complex based on cryo-electron microscopy structures. Important functional regions, such as the intrinsically disordered linker region connecting ACP with the FAS were modeled into the complete complex following extensive molecular dynamics simulations. We used the GROMACS software package to investigate the dynamics of ACP in the presence and absence of the regulatory subunit. Based on these simulations we correlate changes in the dynamics of the carrier domain with changes in enzymatic activity. Overall, our work provides insights into carrier mediated transport in multifunctional enzyme complexes. This process is pivotal to the function of the FAS and presents a key component in optimizing the enzyme for biotechnological application.

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