The ankyrin-repeat and SOCS box protein 9 (ASB9) targets creatine kinases (CK) for degradation, a process crucial to the regulation of ATP/ADP levels at the cell surface of cardiomyocytes. It has been show that the elevation of CK levels in failing mouse hearts increases survival rates threefold. Elevating CK levels in cardiomyocytes in vivo could be achieved by disruption of the CK-ASB9 complex with a small molecule. However, due to the size and structural mobility of intrinsically disordered protein (IDP) complexes like CK-ASB9, X-ray crystallography and NMR spectroscopy, alone, cannot adequately describe such structural ensembles. In this work, multiple lines of experimental data are integrated with computational docking and GPU-enabled simulations to produce a highly accurate model of a large IDP complex. All-atom, explicit-solvent, molecular dynamics (MD) simulations produced a 1.3 μs ensemble of the CK-ASB9 complex, performed on GPUs using the CUDA version of PMEMD in AMBER. From these simulations, a large subset of the total ensemble correlated well with experimental SAXS profiles (χ2 = 0.939) and Rgs, HDX-MS protection factors, ITC enthalpies based on MMGBSA calculations, and mutation data. Where conventional structural biology approaches fail to provide adequate results, high-throughput MD simulations can produce atomistic level trajectories of IDP complexes that are long enough to adequately sample IDP's unique conformational landscape and allow researchers to identify new potential avenues for drug discovery. Such high-throughput simulations are only feasible owing to the enormous speedups provided by GPU-enabled computing.

Entropically driven CK-ASB9 interaction: How GPU-enabled computing provided unique insight into an intrinsically disordered 116 kDa protein complex

249th National Meeting (2015)

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