Functional Significance of Hierarchical Tiers in Carbonmonoxy Myoglobin: Conformational Substates and Transitions Studied by Conformational Flooding Simulations
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- 作者：Brita G. Schulze ; Helmut Grubmü ; ller ; and Jeffrey D. Evanseck
- 刊名：Journal of the American Chemical Society
- 出版年：2000
- 出版时间：September 13, 2000
- 年：2000
- 卷：122
- 期：36
- 页码：8700 - 8711
- 全文大小：441K
- 年卷期：v.122,no.36(September 13, 2000)
- ISSN：1520-5126
文摘
The functional importance of large-scale motions and transitions of carbonmonoxy myoglobin (MbCO)conformational substates (CSs) has been studied by molecular dynamics (MD) and conformational flooding(CF) simulations. A flooding potential was constructed from an 800 ps MD trajectory of solvated MbCO toaccelerate slower protein motions beyond the time scale of contemporary simulations. Two conformationaltransitions (tier-1 substates) resulting from seven principal molecular motions were assigned to the spectroscopicA0 state (tier-0 substate) of MbCO, where His64 is solvated and not within the hydrophobic pocket bindingsite. The first computed conformational transition involves a distal pocket gate defined by the C and D helicesand the interconnecting CD loop (residues 40-55). The gate-like motion is interpreted to regulate ligandaccess from the distal side of the heme. Simultaneously, a proximal pocket lever involving the F helix andsurrounding EF and FG loops (residues 82-105) is found to shuttle the heme deep into the protein matrix(heme rmsd of 3.9 Å) as the distal pocket gate opened. The lever's effect on the heme motion is assumed toattract ligands into the heme pocket. The second major transition involves the compression and expansion ofthe cavity formed by the EF loop (residues 77-84) and the GH loop and H helix (residues 122-138). Themotion is interpreted to modulate the hydrophobic pocket volume and regulate the ligand access from theproximal side of the heme. A third computed conformational transition was found to be a combination of theprevious motions. For the first time, CF was applied in a series of room temperature simulations to acceleratemolecular motions of the MbCO native fold and define the lower tier hierarchy of substate structure. Thecomputed CSs and associated transitions coincide with previously suggested putative ligand escape pathways,and support a hierarchical description of protein dynamics and structure. A unified model that utilizes bothmechanisms of distal His64 modulation (tier-0) and protein equilibrium fluctuations (tier-1) is presented toexplain ligand diffusion in the MbCO dissociation reaction.