Accelerated molecular dynamics simulations of the octopamine receptor using GPUs: discovery of an alternate agonist-binding position.
Octopamine receptors (OARs) perform key biological functions in invertebrates, making this class of G-protein coupled receptors (GPCRs) worth considering for insecticide development. However, no crystal structures and very little research exists for OARs. Furthermore, GPCRs are large proteins, are suspended in a lipid bilayer, and are activated on the millisecond timescale, all of which make conventional molecular dynamics (MD) simulations infeasible, even if run on large supercomputers. However, accelerated Molecular Dynamics (aMD) simulations can reduce this timescale to even hundreds of nanoseconds, while running the simulations on graphics processing units (GPUs) would enable even small clusters of GPUs to have processing power equivalent to hundreds of CPUs. Our results show that aMD simulations run on GPUs can successfully obtain the active and inactive state conformations of a GPCR on this reduced timescale. Furthermore, we discovered a potential alternate active-state agonist-binding position in the octopamine receptor which has yet to be observed and may be a novel GPCR agonist-binding position. These results demonstrate that a complex biological system with an activation process on the millisecond timescale can be successfully simulated on the nanosecond timescale using a simple computing system consisting of a small number of GPUs. Proteins 2016; 84:1480-1489. © 2016 Wiley Periodicals, Inc.
Department of Computer Science and Engineering, University of Notre Dame, Notre Dame, Indiana.
Kevin W
0000-0002-0180-4727
KW
Kastner
Department of Computer Science and Engineering, University of Notre Dame, Notre Dame, Indiana. izaguirr@nd.edu.
Jesús A
JA
Izaguirre
D058666:Adrenergic beta-2 Receptor Agonists / Q000737:chemistry*; D058672:Adrenergic beta-2 Receptor Antagonists / Q000737:chemistry*; D048588:Benzoxazines / Q000737:chemistry*; D003196:Computer Graphics; D006860:Hydrogen Bonding; D008051:Lipid Bilayers / Q000737:chemistry; D056004:Molecular Dynamics Simulation; D010713:Phosphatidylcholines / Q000737:chemistry; D011398:Promethazine / Q000737:chemistry*; D011412:Propanolamines / Q000737:chemistry*; D011485:Protein Binding; D017982:Receptors, Biogenic Amine / Q000737:chemistry*; D040681:Structural Homology, Protein; D013816:Thermodynamics; D013997:Time Factors; D014584:User-Computer Interface
D058666:Adrenergic beta-2 Receptor Agonists; D058672:Adrenergic beta-2 Receptor Antagonists; C584569:BI167107; D048588:Benzoxazines; D008051:Lipid Bilayers; D010713:Phosphatidylcholines; D011412:Propanolamines; D017982:Receptors, Biogenic Amine; C027604:norsynephrine receptor; C014382:carazolol; D011398:Promethazine; C028694:1-palmitoyl-2-oleoylphosphatidylcholine
GPCR; GPCR active and inactive states; aMD simulations; molecular dynamics; octopamine receptor