Single vs. multiple ligand pathways in globins: A computational view

Abstract

Diatomic ligand migration in globins has been the subject of numerous studies. Still, a consensus picture for the ligand entrance is not clear, with a growing concern among experimental researchers that computational simulations always show multiple pathways for any globin. Modeling non-biased ligand entrance from conventional molecular dynamics techniques, however, has shown to be difficult (and expensive). Here we use our Monte Carlo methodology, capable of freely mapping ligand diffusion and the description of rare events, to two well-studied systems: myoglobin and the mini-hemoglobin from the sea worm Cerebratulus lacteus. Our results clearly show that the simulations are specific to the system providing a different trend in the entrance pathway, as expected from experiments. While Mb presents multiple entrance pathways, populating the well-known xenon cavities, in CerHb the ligand enters the protein only by one apolar channel. Most of the trajectories (64%) visiting myoglobin's active site though, are gated by the distal histidine. Such detailed information, accessible through the state of the art algorithms in PELE, is computationally inexpensive and available to all non-profit researchers. This article is part of a Special Issue entitled: Oxygen Binding and Sensing Proteins.