Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 104, Issue 47, Pages 18451-18455Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.0706026104
Keywords
allostery; cooperativity; heme; quantum mechanics/molecular mechanics
Categories
Funding
- NIGMS NIH HHS [GM 33576, R01 GM033576] Funding Source: Medline
Ask authors/readers for more resources
Understanding the molecular mechanism of hemoglobin cooperativity remains an enduring challenge. Protein forces that control ligand affinity are not directly accessible by experiment. We demonstrate that computational quantum mechanics/molecular mechanics methods can provide reasonable values of ligand binding energies in Hb, and of their dependence on allostery. About 40% of the binding energy differences between the relaxed state and tense state quaternary structures result from strain induced in the heme and its ligands, especially in one of the pyrrole rings. The proximal histicline also contributes significantly, in particular, in the a-chains. The remaining energy difference resides in protein contacts, involving residues responsible for locking the quaternary changes. In the alpha-chains, the most important contacts involve the FG corner, at the hinge region of the alpha(1)beta(2) quaternary interface. The energy differences are spread more evenly among the P-chain residues, suggesting greater flexibility for the beta- than for the a-chains along the quaternary transition. Despite this chain differentiation, the chains contribute equally to the relaxed substitute state energy difference. Thus, nature has evolved a symmetric response to the quaternary structure change, which is a requirement for maximum cooperativity, via cliff erent mechanisms f or the two kinds of chains.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available