TY - JOUR
T1 - Molecular basis of co-operativity in protein folding. III. Structural identification of cooperative folding units and folding intermediates
AU - Murphy, Kenneth P.
AU - Bhakuni, Vinod
AU - Xie, Dong
AU - Freire, Ernesto
N1 - Funding Information:
We thank Professor Robert L. Baldwin for helpful comments and Professor S. James Remington for making the refined pepsinogen co-ordinates available before publication. This work was supported by grants from the National Institutes of Health (RR-04328, GM-37911, and NS-24520). K.P.M. and V.B. were also supported by postdoctoral fellowships from the National Science Foundation (DIR-8721059).
PY - 1992/9/5
Y1 - 1992/9/5
N2 - The hierarchical partition function formalism for protein folding developed earlier has been extended through the use of three-dimensional polar and apolar contact plots. For each amino acid residue in the protein, these plots indicate the apolar and polar surfaces that are buried from the solvent, the identity of all amino acid residues that contribute to this shielding, and the magnitude of their contributions. These contact plots are then used to examine the distribution of the free energy of stabilization throughout the protein molecule. Analysis of these data allows identification of co-operative folding units and their hierarchical levels, and the identification of partially folded intermediates with a significant probability of being populated. The overall folding/unfolding thermodynamics of 12 globular proteins, for which crystallographic and experimental thermodynamics are available, is predicted within error. An energetic classification of partially folded intermediates is presented and the results compared to those cases for which structural and thermodynamic experimental information is available. Four different types of partially folded states and their structural energies are considered. (1) Local intermediates, in which only a local region of the protein loses secondary and tertiary interactions, while the rest of the protein remains intact. (2) Global intermediates, corresponding to the standard molten globule definition, in which significant secondary structure is maintained but native-like tertiary structure contacts are disrupted. (3) Extended intermediates characterized by the existence of secondary structure elements (e.g. α-helices) exposed to solvent. (4) Folding intermediates in proteins with two structural domains. The structure and energetics of folding intermediates of apo-myoglobin, α-lactalbumin, phosphoglycerate kinase and arabinose-binding protein are considered in detail.
AB - The hierarchical partition function formalism for protein folding developed earlier has been extended through the use of three-dimensional polar and apolar contact plots. For each amino acid residue in the protein, these plots indicate the apolar and polar surfaces that are buried from the solvent, the identity of all amino acid residues that contribute to this shielding, and the magnitude of their contributions. These contact plots are then used to examine the distribution of the free energy of stabilization throughout the protein molecule. Analysis of these data allows identification of co-operative folding units and their hierarchical levels, and the identification of partially folded intermediates with a significant probability of being populated. The overall folding/unfolding thermodynamics of 12 globular proteins, for which crystallographic and experimental thermodynamics are available, is predicted within error. An energetic classification of partially folded intermediates is presented and the results compared to those cases for which structural and thermodynamic experimental information is available. Four different types of partially folded states and their structural energies are considered. (1) Local intermediates, in which only a local region of the protein loses secondary and tertiary interactions, while the rest of the protein remains intact. (2) Global intermediates, corresponding to the standard molten globule definition, in which significant secondary structure is maintained but native-like tertiary structure contacts are disrupted. (3) Extended intermediates characterized by the existence of secondary structure elements (e.g. α-helices) exposed to solvent. (4) Folding intermediates in proteins with two structural domains. The structure and energetics of folding intermediates of apo-myoglobin, α-lactalbumin, phosphoglycerate kinase and arabinose-binding protein are considered in detail.
KW - co-operativity
KW - folding intermediates
KW - molten globule
KW - protein folding
KW - protein thermodynamics
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U2 - 10.1016/0022-2836(92)90699-K
DO - 10.1016/0022-2836(92)90699-K
M3 - Article
C2 - 1522594
AN - SCOPUS:0026649261
SN - 0022-2836
VL - 227
SP - 293
EP - 306
JO - Journal of molecular biology
JF - Journal of molecular biology
IS - 1
ER -