TY - JOUR
T1 - Protein binding versus protein folding
T2 - The role of hydrophilic bridges in protein associations
AU - Xu, Dong
AU - Lin, Shuo L.
AU - Nussinov, Ruth
N1 - Funding Information:
We thank Drs Dong Xie, Kenneth Murphy, Bruce Tidor, Nir Ban-Tal, Martin Karplus, Rakefet Rosenfeld, Chun-Jung Tsai, Nick Alexandrov, Patrick Rojas, Jie Liang, Shankar Subramaniam and in particular, Dr Jacob Maizel, for helpful discussions. We also thank the personnel at the Frederick Cancer Research and Development Center for their assistance. We are grateful to the two anonymous referees for their constructive suggestions. All the calculations presented in this paper were carried out on Silicon Graphics work stations and Cray-YMP operated by the Frederick Biomedical Supercomputing Center, National Cancer Institute. The research of R.N. has been sponsored by the National Cancer Institute, DHHS, under contract no. 1-CO-74102 with SAIC, and in part by grant no. 95-00208 from the BSF, Israel, by a grant from the Israel Science Foundation administered by the Israel Academy of Sciences, and by the Rekanati Fund. The content of this publication does not necessarily reflect the views or policies of the Department of Human Service, nor does mention of trade names, commercial products, or organizations imply endorsement by the U.S. Government.
PY - 1997/1/10
Y1 - 1997/1/10
N2 - The role of hydrophilic bridges between charged, or polar, atoms in protein associations has been examined from two perspectives. First, statistical analysis has been carried out on 21 data sets to determine the relationship between the binding free energy and the structure of the protein complexes. We find that the number of hydrophilic bridges across the binding interface shows a strong positive correlation with the free energy; second, the electrostatic contribution of salt bridges to binding has been assessed by a continuum electrostatics calculation. In contrast to protein folding, we find that salt bridges across the binding interface can significantly stabilize complexes in some cases. The different contributions of hydrophilic bridges to folding and to binding arise from the different environments to which the involved hydrophilic groups are exposed before and after the bridges are formed. These groups are more solvated in a denatured protein before folding than on the surface of the combining proteins before binding. After binding, they are buried in an environment whose residual composition can be much more hydrophilic than the one after folding. As a result, the desolvation cost of a hydrophilic pair is lower, and the favorable interactions between the hydrophilic pair and its surrounding residues are generally stronger in binding than in folding. These results complement our recent finding that while hydrophobic effect in protein-protein interfaces is significant, it is not as strong as that observed in the interior of monomers. Taken together, these studies suggest that while the types of forces in protein-protein interaction and in protein folding are similar, their relative contributions differ. Hence, association of protein monomers which do not undergo significant conformational change upon binding differs from protein folding, implying that conclusions (e.g. statistics, energetics) drawn from investigating folding may not apply directly to binding, and vice versa.
AB - The role of hydrophilic bridges between charged, or polar, atoms in protein associations has been examined from two perspectives. First, statistical analysis has been carried out on 21 data sets to determine the relationship between the binding free energy and the structure of the protein complexes. We find that the number of hydrophilic bridges across the binding interface shows a strong positive correlation with the free energy; second, the electrostatic contribution of salt bridges to binding has been assessed by a continuum electrostatics calculation. In contrast to protein folding, we find that salt bridges across the binding interface can significantly stabilize complexes in some cases. The different contributions of hydrophilic bridges to folding and to binding arise from the different environments to which the involved hydrophilic groups are exposed before and after the bridges are formed. These groups are more solvated in a denatured protein before folding than on the surface of the combining proteins before binding. After binding, they are buried in an environment whose residual composition can be much more hydrophilic than the one after folding. As a result, the desolvation cost of a hydrophilic pair is lower, and the favorable interactions between the hydrophilic pair and its surrounding residues are generally stronger in binding than in folding. These results complement our recent finding that while hydrophobic effect in protein-protein interfaces is significant, it is not as strong as that observed in the interior of monomers. Taken together, these studies suggest that while the types of forces in protein-protein interaction and in protein folding are similar, their relative contributions differ. Hence, association of protein monomers which do not undergo significant conformational change upon binding differs from protein folding, implying that conclusions (e.g. statistics, energetics) drawn from investigating folding may not apply directly to binding, and vice versa.
KW - Free energy
KW - Hydrophobicity
KW - Protein association
KW - Salt bridge
KW - Solvation effect
UR - http://www.scopus.com/inward/record.url?scp=0031561809&partnerID=8YFLogxK
U2 - 10.1006/jmbi.1996.0712
DO - 10.1006/jmbi.1996.0712
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AN - SCOPUS:0031561809
SN - 0022-2836
VL - 265
SP - 68
EP - 84
JO - Journal of Molecular Biology
JF - Journal of Molecular Biology
IS - 1
ER -