Protein binding versus protein folding: the role of hydrophilic bridges in protein associations 1 1Edited by B. Honig

Xu, Dongyan; Lin, Shuo; Nussinov, Ruth

doi:10.1006/jmbi.1996.0712

Cited by 233 publications

(194 citation statements)

References 84 publications

(121 reference statements)

Supporting

Mentioning

186

Contrasting

Unclassified

Order By: Relevance

“…This mutagenesis data, together with our electrostatic calculations using the CD40L/CD40 structure, suggest that these residues are involved in ion pairs that are stabilizing the complex. Our data are in accordance with that of Xu et al (1997), who have studied the general importance of ion pairs in stabilizing protein-protein interfaces. They show through the use of continuum electrostatic calculations on X-ray structures of protein complexes that salt bridges can significantly stabilize protein interfaces.…”

Section: Discussionsupporting

confidence: 92%

“…They show through the use of continuum electrostatic calculations on X-ray structures of protein complexes that salt bridges can significantly stabilize protein interfaces. The importance of hydrophilic pair interactions in stabilizing protein-protein complexes has also been studied by Xu et al (1997). They found a positive correlation between free energy of complex formation and the number of hydrophilic bridges across an interface in an analysis of known three-dimensional structures of protein complexes.…”

Section: Discussionmentioning

confidence: 99%

“…We used the method described by Hendsch and Tidor (1994) and Xu et al (1997). The method consists of calculating the difference in total electrostatic free energy between the residue pair in the complex and in the separate proteins.…”

Section: Electrostatic Analysismentioning

confidence: 99%

See 2 more Smart Citations

The role of polar interactions in the molecular recognition of CD40L with its receptor CD40

et al. 1998

View full text Add to dashboard Cite

CD40 Ligand (CD40L) is transiently expressed on the surface of T-cells and binds to CD40, which is expressed on the surface of B-cells. This binding event leads to the differentiation, proliferation, and isotype switching of the B-cells. The physiological importance of CD40L has been demonstrated by the fact that expression of defective CD40L protein causes an immunodeficiency state characterized by high IgM and low IgG serum levels, indicating faulty T-cell dependent B-cell activation. To understand the structural basis for CD40L/CD40 association, we have used a combination of molecular modeling, mutagenesis, and X-ray crystallography. The structure of the extracellular region of CD4OL was determined by protein crystallography, while the CD40 receptor was built using homology modeling based upon a novel alignment of the TNF receptor superfamily, and using the X-ray structure of the TNF receptor as a template. The model shows that the interface of the complex is composed of charged residues, with CD4OL presenting basic side chains (K143, R203, R207), and CD40 presenting acidic side chains (D84, El 14, E l 17). These residues were studied experimentally through site-directed mutagenesis, and also theoretically using electrostatic calculations with the program Delphi. The mutagenesis data explored the role of the charged residues in both CD40L and CD40 by switching to Ala (K143A, R203A, R207A of CD40L, and E74A, D84A, El14A, E l 17A of CD40), charge reversal (K143E, R203E, R207E of CD40L, and D84R, E l 14R, El 17R of CD40), mutation to a polar residue (K143N, R207N, R207Q of C340L, and D84N, E l 17N of CD40), and for the basic side chains in CD40L, isosteric substitution to a hydrophobic side chain (R203M, R207M). All the charge-reversal mutants and the majority of the Met and Ala substitutions led to loss of binding, suggesting that charged interactions stabilize the complex. This was supported by the Delphi calculations which confirmed that the CD40/CD40L residue pairs E74-R203, D84-R207, and El 17-R207 had a net stabilizing effect on the complex. However, the substitution of hydrophilic side chains at several of the positions was tolerated, which suggests that although charged interactions stabilize the complex, charge per se is not crucial at all positions. Finally, we compared the electrostatic surface of TNFjTNFR with CD40L/CD40 and have identified a set of polar interactions surrounded by a wall of hydrophobic residues that appear to be similar but inverted between the two complexes.

show abstract

Section: Discussionsupporting

confidence: 92%

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

The role of polar interactions in the molecular recognition of CD40L with its receptor CD40

et al. 1998

View full text Add to dashboard Cite

show abstract

“…This loss of water, or desolvation, is generally energetically unfavorable and offsets the favorable interactions formed upon binding. The binding affinities, from an electrostatic point of view, are determined by balance of these two energetic contributions (Xu et al, 1997;Lee and Tidor, 2001;Sheinerman and Honig, 2002;Russell et al, 2004;del Álamo and Mateu, 2005). Systematic studies of protein pairs, such as barnase and barstar Fersht, 1993, 1995;Frisch et al, 1997;Dong et al, 2003), and fasciculin-2 (Radic et al, 1997), as well as protein kinase A and balanol (Wong et al, 2001), have shown that charged and polar residues at the protein-protein interfaces play important roles in binding energetics.…”

Section: Iib Biomolecule-ligand and -Biomolecule Interactionsmentioning

confidence: 99%

Computational Methods for Biomolecular Electrostatics

Dong

Olsen

Baker

2008

Methods in Cell Biology

116

View full text Add to dashboard Cite

An understanding of intermolecular interactions is essential for insight into how cells develop, operate, communicate and control their activities. Such interactions include several components: contributions from linear, angular, and torsional forces in covalent bonds, van der Waals forces, as well as electrostatics. Among the various components of molecular interactions, electrostatics are of special importance because of their long range and their influence on polar or charged molecules, including water, aqueous ions, and amino or nucleic acids, which are some of the primary components of living systems. Electrostatics, therefore, play important roles in determining the structure, motion and function of a wide range of biological molecules. This chapter presents a brief overview of electrostatic interactions in cellular systems with a particular focus on how computational tools can be used to investigate these types of interactions.

show abstract

“…In fact, Xu et al showed that a simple number count of hydrophilic bridges across the binding interface is strongly correlated with binding free energies of protein-protein interaction (Xu et al, 1997). This study suggests that binding free energy may be predicted successfully by number counts of various types of interfacial contacts defined using some distance threshold.…”

Section: Protein Stability and Binding Affinitymentioning

confidence: 83%

Knowledge-Based Energy Functions for Computational Studies of Proteins

Li¹,

Liang²

Biological and Medical Physics Biomedical Engineering

View full text Add to dashboard Cite

Protein binding versus protein folding: the role of hydrophilic bridges in protein associations 1 1Edited by B. Honig

Cited by 233 publications

References 84 publications

The role of polar interactions in the molecular recognition of CD40L with its receptor CD40

The role of polar interactions in the molecular recognition of CD40L with its receptor CD40

Computational Methods for Biomolecular Electrostatics

Knowledge-Based Energy Functions for Computational Studies of Proteins

Contact Info

Product

Resources

About