We
present a supercomputer-driven pipeline for in silico drug discovery
using enhanced sampling molecular dynamics (MD) and ensemble docking.
Ensemble docking makes use of MD results by docking compound databases
into representative protein binding-site conformations, thus taking
into account the dynamic properties of the binding sites. We also
describe preliminary results obtained for 24 systems involving eight
proteins of the proteome of SARS-CoV-2. The MD involves temperature
replica exchange enhanced sampling, making use of massively parallel
supercomputing to quickly sample the configurational space of protein
drug targets. Using the Summit supercomputer at the Oak Ridge National
Laboratory, more than 1 ms of enhanced sampling MD can be generated
per day. We have ensemble docked repurposing databases to 10 configurations
of each of the 24 SARS-CoV-2 systems using AutoDock Vina. Comparison
to experiment demonstrates remarkably high hit rates for the top scoring
tranches of compounds identified by our ensemble approach. We also
demonstrate that, using Autodock-GPU on Summit, it is possible to
perform exhaustive docking of one billion compounds in under 24 h.
Finally, we discuss preliminary results and planned improvements to
the pipeline, including the use of quantum mechanical (QM), machine
learning, and artificial intelligence (AI) methods to cluster MD trajectories
and rescore docking poses.
BackgroundThe conversion of plant biomass to ethanol via enzymatic cellulose hydrolysis offers a potentially sustainable route to biofuel production. However, the inhibition of enzymatic activity in pretreated biomass by lignin severely limits the efficiency of this process.ResultsBy performing atomic-detail molecular dynamics simulation of a biomass model containing cellulose, lignin, and cellulases (TrCel7A), we elucidate detailed lignin inhibition mechanisms. We find that lignin binds preferentially both to the elements of cellulose to which the cellulases also preferentially bind (the hydrophobic faces) and also to the specific residues on the cellulose-binding module of the cellulase that are critical for cellulose binding of TrCel7A (Y466, Y492, and Y493).Conclusions Lignin thus binds exactly where for industrial purposes it is least desired, providing a simple explanation of why hydrolysis yields increase with lignin removal.Electronic supplementary materialThe online version of this article (doi:10.1186/s13068-015-0379-8) contains supplementary material, which is available to authorized users.
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