Chemical properties of alcohols and their protein binding sites

Abstract

Alcohols affect a wide array of biological processes including protein folding, neurotransmission and immune responses. It is becoming clear that many of these effects are mediated by direct binding to proteins such as neurotransmitter receptors and signaling molecules. This review summarizes the unique chemical properties of alcohols which contribute to their biological effects. It is concluded that alcohols act mainly as hydrogen bond donors whose binding to the polypeptide chain is stabilized by hydrophobic interactions. The electronegativity of the O atom may also play a role in stabilizing contacts with the protein. Properties of alcohol binding sites have been derived from X-ray crystal structures of alcohol-protein complexes and from mutagenesis studies of ion channels and enzymes that bind alcohols. Common amino acid sequences and structural features are shared among the protein segments that are involved in alcohol binding. The alcohol binding site is thought to consist of a hydrogen bond acceptor in a turn or loop region that is often situated at the N-terminal end of an alpha-helix. The methylene chain of the alcohol molecule appears to be accommodated by a hydrophobic groove formed by two or more structural elements, frequently a turn and an alpha-helix. Binding at these sites may alter the local protein structure or displace bound solvent molecules and perturb the function of key proteins.

Geometric Isomers of a Photoactivable General Anesthetic Delineate a Binding Site on Adenylate Kinase

“…For example, in firefly luciferase, one of the binding pockets for the anesthetic bromoform includes histidine, arginine, threonine, and two glutamic acids (5). Our results are in partial agreement with a recent analysis that concluded that alcohol binding sites possess a hydrogen bond acceptor in a turn or loop often located near the Nterminal end of an ␣-helix (35). The location of anesthetic sites at the interface between two structural domains has been noted in some other cases (6,36) and may prove to be a common motif for general anesthetic binding sites.…”

Structure of a specific alcohol-binding site defined by the odorant binding protein LUSH from Drosophila melanogaster

“…This mode of alcohol binding is unrelated to the non-enzymatic sites that occur in alcohol-sensitive ion-channels. Information from an analysis of protein crystal structures solved using alcohols as cosolvents revealed that H-bonds between the alcohol and protein are formed predominantly with atoms in the protein backbone 18 . These are non-specific interactions (i.e.…”

“…A blood alcohol level of 0.1%, the legal limit for driving in many US states, corresponds to a concentration of ~22 mM. Structural and biophysical studies of anesthetics bound to model proteins have defined the importance of both non-polar and polar groups in the binding sites of these molecules [19][20][21][22][23] and binding sites for alcohols will also posses such an amphipathic nature 18 .…”

Molecular Features of an Alcohol Binding Site in a Neuronal Potassium Channel

“…The results of these studies are consistent with the presence of physically circumscribed hydrophobic protein cavities that constitute the alcohol and general anesthetic sites. Also, studies with soluble model proteins have examined the relationship between anesthetic solubility and anesthetic action along with structure-function analysis and thermodynamic arguments and suggest that polar interactions also contribute to the binding of alcohol and inhaled anesthetics (5,9,(12)(13)(14)(15). Polar interactions are also likely to contribute to the binding of general anesthetic agents to ion channels, which are critical physiological targets of these agents (including 1-alkanols).…”