TY - JOUR
T1 - Identifying protein folding cores from the evolution of flexible regions during unfolding
AU - Hespenheide, Brandon M.
AU - Rader, A. J.
AU - Thorpe, M. F.
AU - Kuhn, Leslie A.
N1 - Funding Information:
We would like to thank Clare Woodward for valuable discussions during the early stages of this work. We also thank the MSU Center for Protein Structure, Function, and Design, the MSU Center for Biological Modeling, and the Barnett C. Rosenberg Fellowship for support to B.M.H. and A.J.R., and the NSF for support under Grants DBI-9600831 and DMR-0078361.
Copyright:
Copyright 2008 Elsevier B.V., All rights reserved.
PY - 2002/12
Y1 - 2002/12
N2 - The unfolding of a protein can be described as a transition from a predominantly rigid, folded structure to an ensemble of denatured states. During unfolding, the hydrogen bonds and salt bridges break, destabilizing the secondary and tertiary structure. Our previous work shows that the network of covalent bonds, salt bridges, hydrogen bonds, and hydrophobic interactions forms constraints that define which regions of the native protein are flexible or rigid (structurally stable). Here, we test the hypothesis that information about the folding pathway is encoded in the energetic hierarchy of non-covalent interactions in the native-state structure. The incremental thermal denaturation of protein structures is simulated by diluting the network of salt bridges and hydrogen bonds, breaking them one by one, from weakest to strongest. The structurally stable and flexible regions are identified at each step, providing information about the evolution of flexible regions during denaturation. The folding core, or center of structure formation during folding, is predicted as the region formed by two or more secondary structures having the greatest stability against denaturation. For 10 proteins with different architectures, we show that the predicted folding cores from this flexibility/stability analysis are in good agreement with those identified by native-state hydrogen-deuterium exchange experiments.
AB - The unfolding of a protein can be described as a transition from a predominantly rigid, folded structure to an ensemble of denatured states. During unfolding, the hydrogen bonds and salt bridges break, destabilizing the secondary and tertiary structure. Our previous work shows that the network of covalent bonds, salt bridges, hydrogen bonds, and hydrophobic interactions forms constraints that define which regions of the native protein are flexible or rigid (structurally stable). Here, we test the hypothesis that information about the folding pathway is encoded in the energetic hierarchy of non-covalent interactions in the native-state structure. The incremental thermal denaturation of protein structures is simulated by diluting the network of salt bridges and hydrogen bonds, breaking them one by one, from weakest to strongest. The structurally stable and flexible regions are identified at each step, providing information about the evolution of flexible regions during denaturation. The folding core, or center of structure formation during folding, is predicted as the region formed by two or more secondary structures having the greatest stability against denaturation. For 10 proteins with different architectures, we show that the predicted folding cores from this flexibility/stability analysis are in good agreement with those identified by native-state hydrogen-deuterium exchange experiments.
KW - Apo-myoglobin
KW - Barnase
KW - Bovine pancreatic trypsin inhibitor
KW - Cytochrome c
KW - Flexibility modeling
KW - Folding nucleus
KW - Folding pathways
KW - Graph theory
KW - Hydrogen bond networks
KW - Hydrogen-exchange NMR
KW - Ribonuclease T1
KW - Structural stability
KW - Thermal denaturation
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U2 - 10.1016/S1093-3263(02)00146-8
DO - 10.1016/S1093-3263(02)00146-8
M3 - Article
C2 - 12463638
AN - SCOPUS:0036888379
SN - 1093-3263
VL - 21
SP - 195
EP - 207
JO - Journal of Molecular Graphics and Modelling
JF - Journal of Molecular Graphics and Modelling
IS - 3
ER -