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Locally enhanced sampling molecular dynamics study of the dioxygen transport in human cytoglobin

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Abstract

Cytoglobin (Cyg)—a new member of the vertebrate heme globin family—is expressed in many tissues of the human body but its physiological role is still unclear. It may deliver oxygen under hypoxia, serve as a scavenger of reactive species or be involved in collagen synthesis. This protein is usually six-coordinated and binds oxygen by a displacement of the distal HisE7 imidazole. In this paper, the results of 60 ns molecular dynamics (MD) simulations of dioxygen diffusion inside Cyg matrix are discussed. In addition to a classical MD trajectory, an approximate Locally Enhanced Sampling (LES) method has been employed. Classical diffusion paths were carefully analyzed, five cavities in dynamical structures were determined and at least four distinct ligand exit paths were identified. The most probable exit/entry path is connected with a large tunnel present in Cyg. Several residues that are perhaps critical for kinetics of small gaseous diffusion were discovered. A comparison of gaseous ligand transport in Cyg and in the most studied heme protein myoglobin is presented. Implications of efficient oxygen transport found in Cyg to its possible physiological role are discussed.

Pathways P3 (green), P3′ (red) and P3″ (blue). These pathways are located between G and H helices. Ligand moved from CavXe2Xe3 cavity to solvent using gateP3, gateP3′ or gateP3″. A detailed picture of the CavXe2Xe3 is available in Electronic Supplementary Materials (Fig. S13). CavXe2Xe3 constitute the main part of wide hydrophobic tunnel

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Acknowledgements

This work was supported by grant “Krok w przyszlosc-stypendia dla doktorantow” (S.O.), President of Poland grant “Superpracownia 2002” and in part by MEiN grant 2P04A 07229 (W.N.). We thank CI TASK for computer time and Albert Rutkowski for his assistance in computations.

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Authors and Affiliations

  1. Theoretical Molecular Biophysics Group, Institute of Physics, Nicolaus Copernicus University, ul. Grudziadzka 5, 87-100, Torun, Poland

    Slawomir Orlowski & Wieslaw Nowak

Authors
  1. Slawomir Orlowski
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  2. Wieslaw Nowak
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Correspondence to Wieslaw Nowak.

Electronic supplementary material

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Fig. S1

RMSD analysis of all trajectories. The calculations were performed on Cα atoms using the initial structure as a reference. The blue plot represents the standard (LES1) trajectory. Black, red and green plots are from LES5, LES10 and LES15 trajectories, respectively (GIF 20 kb)

High resolution image file (TIF 451 kb)

Fig. S2

Energy plots for the standard (LES1) trajectory, divided into total energy (black), kinetic (red) and potential (blue). The simulations are energetically stable (GIF 7 kb)

High resolution image file (EPS 1871 kb)

Fig. S3

Energy plots for the LES5 trajectory, divided into total energy (black), kinetic (red) and potential (blue). The simulations are energetically stable (GIF 7 kb)

High resolution image file (EPS 1863 kb)

Fig. S4

Energy plots for the LES10 trajectory, divided into total energy (black), kinetic (red) and potential (blue). The simulations are energetically stable (GIF 7 kb)

High resolution image file (EPS 1870 mb)

Fig. S5

Energy plots for the LES15 trajectory, divided into total energy (black), kinetic (red) and potential (blue). The simulations are energetically stable (GIF 7 kb)

High resolution image file (EPS 1874 kb)

Fig. S6

Temperature observed in the standard (LES1) trajectory. A value of the temperature achieved stabilization. The mean temperature is 299.72 ± 2.06 K (GIF 29 kb)

High resolution image file (EPS 1536 kb)

Fig. S7

Temperature observed in the LES5 trajectory. A value of the temperature achieved stabilization. The mean temperature is 299.74 ± 2.07 K (GIF 7 kb)

High resolution image file (EPS 1862 kb)

Fig. S8

Temperature observed in the LES10 trajectory. A value of the temperature achieved stabilization. The mean temperature is 299.74 ± 2.07 K (GIF 7 kb)

High resolution image file (EPS 1870 kb)

Fig. S9

Temperature observed in the LES15 trajectory. A value of the temperature achieved stabilization. The mean temperature is 299.74 ± 2.09 K (GIF 7 kb)

High resolution image file (EPS 1874 kb)

Fig. S10

Amino acids composition of the heme cavity (HemeCav). All phenylalanine residues are represented in red, leucines are displayed in green, Val85 in blue and His81 in yellow. The cytoglobin surface is represented in blue and the heme group with the proximal histidine is black (GIF 158 kb)

High resolution image file (TIF 2501 kb)

Fig. S11

All amino acids whose participate in building of the Xe1 cavity (CavXe1). All leucines are displayed in green and rest of the amino acids are properly labeled. The cytoglobin surface is represented in blue and the heme group with the proximal histidine is black (GIF 176 kb)

High resolution image file (TIF 2319 kb)

Fig. S12

All amino acids whose participate in building of the Xe4 cavity (CavXe4). The Cyg surface is represented in blue and the heme group with the proximal histidine is black (GIF 143 kb)

High resolution image file (TIF 2294 kb)

Fig. S13

All amino acids whose participate in building of the Xe2 Xe3 cavity (CavXe2Xe3). The color scheme is the same as on S10–S12 figures. Residue Ser128 is represented in pink, Val 93 is blue. The Cyg surface is represented in blue and the heme group with the proximal histidine is black (GIF 155 kb)

High resolution image file (TIF 2479 kb)

Fig. S14

All amino acids whose participate in building of the FE cavity (CavFE). The color scheme is the same as on previous figures. Residue Phe124 is represented in pink. The Cyg surface is represented in blue and the heme group with the proximal histidine is black (GIF 179 kb)

High resolution image file (TIF 2352 kb)

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Orlowski, S., Nowak, W. Locally enhanced sampling molecular dynamics study of the dioxygen transport in human cytoglobin. J Mol Model 13, 715–723 (2007). https://doi.org/10.1007/s00894-007-0203-x

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