In the family of respiratory proteins, hemoglobins and myoglobins have been the first to be crystallized in '50. Despite their precise 3D structures are available at high resolution, some questions regarding the microscopic functioning remain yet open. The R to T switching mechanism in hemoglobins and the ligand escape process in myoglobins remain still under debate. Thanks to the small size, myoglobin is the preferred candidate also for the more general structure-funcion paradigm. In the interior of myoglobin five main docking sites have been identified, especially with Xe NMR, and for long time these Xenon cavities have been classified as packing defects. Recently, it was shown that they might be involved in ligands migration path, even if mechanisms used by myoglobin to connect these cavities is still unknown as well as processes regulating its biologic functions. In this work we made use of standard MD simulations of solvated myoglobin to characterize internal cavities. Our principal results is that we have found several secondary cavities showing volume and occurrence at least comparable to that of Xenon cavities. In order to rationalize and in-depth analyze such a huge amount of data (ca. 30000 cavities/10 ns MD), special cluster-analysis was applied: we classified all cavities with respect to the position, size and occurrence as function of simulation time ascribing them to different clusters. This analysis implicitly highlights possible ligand migration paths for small ligands within the protein matrix allowing to quantitatively compare dynamical behaviour of different myoglobins towards different ligands. Our suggestion that the secondary cavities constitute the preferred path for ligand escape is also supported by explicit metadynamics simulations of ligand escape.
Structural analysis of hemoglobins and myoglobins using MD simulations
SCORCIAPINO, MARIANO ANDREA;CASU, MARIANO;RUGGERONE, PAOLO;CECCARELLI, MATTEO
2009-01-01
Abstract
In the family of respiratory proteins, hemoglobins and myoglobins have been the first to be crystallized in '50. Despite their precise 3D structures are available at high resolution, some questions regarding the microscopic functioning remain yet open. The R to T switching mechanism in hemoglobins and the ligand escape process in myoglobins remain still under debate. Thanks to the small size, myoglobin is the preferred candidate also for the more general structure-funcion paradigm. In the interior of myoglobin five main docking sites have been identified, especially with Xe NMR, and for long time these Xenon cavities have been classified as packing defects. Recently, it was shown that they might be involved in ligands migration path, even if mechanisms used by myoglobin to connect these cavities is still unknown as well as processes regulating its biologic functions. In this work we made use of standard MD simulations of solvated myoglobin to characterize internal cavities. Our principal results is that we have found several secondary cavities showing volume and occurrence at least comparable to that of Xenon cavities. In order to rationalize and in-depth analyze such a huge amount of data (ca. 30000 cavities/10 ns MD), special cluster-analysis was applied: we classified all cavities with respect to the position, size and occurrence as function of simulation time ascribing them to different clusters. This analysis implicitly highlights possible ligand migration paths for small ligands within the protein matrix allowing to quantitatively compare dynamical behaviour of different myoglobins towards different ligands. Our suggestion that the secondary cavities constitute the preferred path for ligand escape is also supported by explicit metadynamics simulations of ligand escape.
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