Cellular protein quality control plays a critical role in maintaining cell viability by recognizing and degrading misfolded proteins to prevent toxic protein aggregation. Powerful AAA+ ATPases, such as ClpY, form hexameric macromolecular structures which selectively process abnormal proteins that are targeted for degradation by unfolding and threading them through a narrow central channel. The molecular details of unfolding and translocation of substrate proteins by these nanomachines are not yet fully understood. Here, we perform GPU-accelerated molecular dynamics simulations of the ClpYΔI ATPase and Titin I27 in the presence of water molecules with the system size of 300k atoms. We reach the timescale of our previous CPU-based coarse-grained simulations by using GPU-accelerated simulations. The presence of water molecules allows us to decipher the details of unfolding and translocation of SP mediated by ClpYΔI ATPase with atomic resolution. Cyclical opening and closing of the ClpYΔI ring are modeled through sequential conformational changes of ClpYΔI subunits by using OpenMM and NAMD on NVIDIA GPU architectures. We find that central pore loops form hydrogen bond with SP backbone during translocation process, and cyclical “open” and “closed” configurations of the central pore promote SP threading via direction-dependent unfolding.

GPU-accelerated molecular dynamics simulations of protein remodeling mediated by AAA+ biological nanomachines

254th National Meeting (2017)

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