ArticleProceedings of the National Academy of Sciences of the United States of America1998
Electrostatic steering and ionic tethering in enzyme-ligand binding: insights from simulations.
Article in Proceedings of the National Academy of Sciences of the United States of America, 1998. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 86 papers.
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86 citing papers in PubMed.
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- Searching for Hydrodynamic Orienting Effects in the Association of Tri-The journal of physical chemistry. B · 2021Article
- Kinetic and Structural Characterization of the Self-Labeling Protein Tags HaloTag7, SNAP-tag, and CLIP-tag.Biochemistry · 2021Article
- Mechanism of Ligand Recognition by Human ACE2 Receptor.The journal of physical chemistry letters · 2021Article
- New structural insights reveal an expanded reaction cycle for inositol pyrophosphate hydrolysis by human DIPP1.FASEB journal : official publication of the Federation of American Societies for Experimental Biology · 2021Article
- Identification of the Primary Factors Determining theSpecificity of Human VKORC1 Recognition by Thioredoxin-Fold Proteins.International journal of molecular sciences · 2021Article
26 more citing papers are in PubMed but not listed here.
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4 authors.
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Abstract
To bind at an enzyme's active site, a ligand must diffuse or be transported to the enzyme's surface, and, if the binding site is buried, the ligand must diffuse through the protein to reach it. Although the driving force for ligand binding is often ascribed to the hydrophobic effect, electrostatic interactions also influence the binding process of both charged and nonpolar ligands. First, electrostatic steering of charged substrates into enzyme active sites is discussed. This is of particular relevance for diffusion-influenced enzymes. By comparing the results of Brownian dynamics simulations and electrostatic potential similarity analysis for triose-phosphate isomerases, superoxide dismutases, and beta-lactamases from different species, we identify the conserved features responsible for the electrostatic substrate-steering fields. The conserved potentials are localized at the active sites and are the primary determinants of the bimolecular association rates. Then we focus on a more subtle effect, which we will refer to as "ionic tethering." We explore, by means of molecular and Brownian dynamics simulations and electrostatic continuum calculations, how salt links can act as tethers between structural elements of an enzyme that undergo conformational change upon substrate binding, and thereby regulate or modulate substrate binding. This is illustrated for the lipase and cytochrome P450 enzymes. Ionic tethering can provide a control mechanism for substrate binding that is sensitive to the electrostatic properties of the enzyme's surroundings even when the substrate is nonpolar.
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