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Anesth Analg 2007;104:318-324 © 2007 International Anesthesia Research Society doi: 10.1213/01.ane.0000253029.67331.8d
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Abstract |
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 Top Abstract IntroductionMETHODSRESULTSDISCUSSIONCONCLUSIONSREFERENCES |
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BACKGROUND: It is not yet possible to obtain crystal structures of anesthetic molecules bound to proteins that are plausible neuronal targets; for example, ligand-gated ion channels. However, there are x-ray crystal structures in which anesthetics are complexed with proteins that are not directly related to anesthetic action. Much useful information about anesthetic–protein interactions can be derived from the x-ray crystal structures of halothane–cholesterol oxidase, bromoform–luciferase, halothane–albumin, and dichloroethane–dehalogenase. These structures show anesthetic-protein interactions at the atomic level.
METHODS: We obtained the known coordinate files for bromoform–luciferase, halothane– albumin, dichloroethane–dehalogenase, and halothane–cholesterol oxidase. These were then modified by adding hydrogens, edited into subsets, and underwent a series of restrained molecular mechanics optimizations. Final analysis of anesthetic polarization within the anesthetic binding site occurred via combined molecular mechanics–quantum mechanics calculations.
RESULTS: The anesthetic binding sites within these well-characterized anesthetic– protein complexes possess a set of common characteristics that we refer to as "binding motifs." The common features of these motifs are polar and nonpolar interactions within an amphiphilic binding cavity, including the presence of weak hydrogen bond interactions with amino acids and water molecules. Calculations also demonstrated the polarizing effect of the amphipathic binding sites on what are otherwise considered quite hydrophobic anesthetics. This polarization appears energetically favorable.
CONCLUSIONS: Anesthetic binding to proteins involves amphipathic interactions.
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Introduction |
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TopAbstractIntroductionMETHODSRESULTSDISCUSSIONCONCLUSIONSREFERENCES |
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For more than 160 yr, general anesthesia has provided pain-free surgery. Early investigations into the mechanisms of anesthetic action by Meyer and Overton (1,2) demonstrated a good correlation of anesthetic potency with partitioning into olive oil. For most of the 20th century, the Meyer–Overton correlation of anesthetic potency with lipid solubility remained a robust physical phenomenon. However, hypotheses involving the direct nonpolar effects of anesthetics on lipid bilayers and their postulated indirect effects on synaptic transmission and subsequent behavior have not been fully explanatory (3–5). Moreover, Koblin et al. (6) have clearly demonstrated several classes of compounds that deviate from the Meyer–Overton correlation. These include several polyhalogenated linear and cyclic hydrocarbons whose lipid solubilities would predict reasonable anesthetic potency but which are without significant anesthetic effect. In particular, with regard to the alveolar partial pressure of anesthetic gas required to suppress a purposeful response to surgical incision in 50% of the patient population (minimum alveolar concentration), these substances can be classified as those with partial anesthetic effect (the transitional compounds) and those with no effect at all (the nonimmobilizers). In fact, within the series of transitional anesthetic compounds, potency correlates with the polarity of a compound, and not its nonpolarity or lipophilicity (6). In addition to these exceptions, the different potencies of many optical isomers of anesthetics have defied explanation in terms of olive oil or lipid partitioning (7–9).
Other investigations into the direct effect of anesthetics on synaptic ion channel proteins have proven quite fruitful (5). Mutational analyses of ligand-gated ion channels (LGICs) such as the nicotinic acetylcholine receptor, the glycine 
-1 receptor (GlyR1) and the 
-aminobutyric acid receptor (GABAAR) have demonstrated that there are possible sites of anesthetic action within their transmembrane domains (10,11). To understand the actual mechanism of anesthesia, and possibly design better anesthetics, one would like to have knowledge of the exact molecular interactions between an anesthetic and its protein-binding site. Unfortunately, high-resolution x-ray crystal structures for these LGICs are not yet possible. However, a combination of molecular modeling techniques and experimental data has provided a plausible model of an anesthetic binding site within the GABAAR and GlyR1 transmembrane domains (12,13). These models have revealed putative anesthetic binding sites with both polar and nonpolar characteristics.
While it has not been possible to obtain crystal structures of anesthetic molecules within these LGICs, there are x-ray crystal structures in which anesthetics are complexed with other proteins that are unrelated to synaptic transmission. Since most general anesthetics are relatively small molecules, we may derive relevant information on how anesthetics bind to proteins in general from an examination of such high-resolution crystal structures. These crystal structures, with atomic level precision, include halothane–cholesterol oxidase,1 bromoform–luciferase (14), halothane–albumin (15), and dichloroethane–dehalogenase (16). For each publication involving a given set of coordinates, a variety of chemical environments in which anesthetics bind has been described. These environments have both nonpolar and polar components, suggesting an amphipathic binding site. Using molecular modeling and computational chemistry techniques, we now demonstrate the similarities of such chemical binding environments across all four sets of coordinates. We also discuss a common set of binding interactions between chemical moieties or "binding motifs." In particular, we quantify the proximity of nonpolar residues available for van der Waals types of interactions and the proximity of polar residues available for both polar and weak hydrogen bond interactions. Finally, and most importantly, using quantum mechanics combined with molecular mechanics (QM-MM) techniques, we demonstrate, for the first time, the clear polarizing effect that an amphipathic binding site has upon otherwise nonpolar anesthetic ligands. We review the implications of these motifs for a more general understanding of anesthetic action.
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METHODS |
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Summary of Methods
Each protein–anesthetic complex that was studied had initial atomic coordinates available from previous work via x-ray crystallography. While these coordinates are of relatively high resolution, further refinement of the exact coordinates of atoms in both the anesthetic and the protein within each complex was necessary for the proper analysis of the anesthetic– protein interactions. This was accomplished using computational chemistry tools, specifically, molecular mechanics and quantum mechanics. Such tools allowed energy optimization of the structures based on a comprehensive set of both covalent and noncovalent interatomic interactions. Furthermore, these tools allow for the addition of water molecules into spaces within the anesthetic–protein complex that may otherwise not be readily discernible by x-ray crystallographic means. Because water molecules within proteins are not all resolved by crystallographic analysis, they are often omitted from the refined crystal structure. As a result, it is essential for us to add appropriate water molecules to cavities using a solvation algorithm. Once solvated and refined, further QM calculations were performed to clearly delineate the polarization effect of an amphipathic binding site upon the anesthetic ligand.
Methods in Detail
All calculations were performed using Hyperchem 7.5 (Hypercube, Gainesville, FL). The protein databank (PDB) coordinate files for bromoform–luciferase (PDB ID 1BA3), halothane–albumin (PDB ID 1E7B), and dichloroethane–dehalogenase (PDB ID 2DHC) were obtained from the Research Collaboratory for Structural Biology. The coordinates for the cholesterol oxidase–halothane complex were obtained from the labs of Drs. Peter Brick and Nick Franks.1 Each PDB file went through a similar sequence of preparation prior to analysis: adding hydrogens, setting MM parameters with the AMBER force field (17), and defining subsets for subsequent analysis. Stepwise energy optimizations of hydrogens to a gradient of 1.0 kcal/mol · Å with the steepest descents algorithm were followed with further optimization using the Polak– Ribiere algorithm to a gradient of 0.1 kcal/mol · Å (18). The system was then divided into a QM region (anesthetic ligand) and a MM region (the protein, the waters, and any additional ligands). The partial charges on the anesthetic ligands were then calculated using the combined QM-MM calculation features within Hyperchem [AM1 semiempirical parameters for QM (19) and AMBER parameters for MM]. The hydrogens were then reoptimized with AMBER parameters and the Polak–Ribiere algorithm to a gradient of 0.1 kcal/mol · Å. A region within 10 Å of the anesthetic was carved out of each complex and hydrated in a periodic water box filled with water molecules (we used the dimensions and partial atomic charges for water molecules known as TIP3P). Initially, the periodic box was completely filled with water molecules and then any waters that touched the protein or ligand within a cutoff radius of 1.8 Å were removed. As a test of this solvation algorithm, we removed all waters present in the crystal structure of ligand-free cholesterol oxidase (PDB ID 3COX). This cutoff radius for water molecules reproduced the 13 waters seen in the main cavity of the crystal structure. Any water molecules added to the crystal structures were then optimized as above with all other atomic coordinates fixed. Final polarization of the anesthetic caused by binding was calculated within the cavity using a QM-MM calculation with AM1 semiempirical parameters embedded in the surrounding MM charges. In the cases with two ligand molecules bound, only one anesthetic binding site was chosen for analysis within each anesthetic–protein complex. Calculation of partial atomic charges on the anesthetic was accomplished via the Mulliken partitioning scheme.
The anesthetic was then removed from the protein complex and placed in vacuo. A single-point MM energy was calculated for the anesthetic in vacuo with the charges derived from its polarization within the protein binding cavity. The anesthetic then underwent a process of optimization with the AM1 semiempirical parameters (19) and the Polak–Ribiere method to a gradient of 0.1 kcal/mol · Å. Calculation of new partial atomic charges on the anesthetic was accomplished via the Mulliken partitioning scheme. The new single-point MM energy was then calculated for the ligand with its geometry and charges derived from in vacuo AM1 optimization. The resulting change in partial atomic charges demonstrated the degree of anesthetic polarization within the binding cavity.
We wanted to calculate the overall favorable energy that resulted from polarization of the anesthetic within the anesthetic–protein complex by the amphipathic binding site. To determine this, single point energy calculations were performed on the hydrated anesthetic–protein complex with the QM-MM derived anesthetic in situ charges (polarized), and then with the optimized in vacuo anesthetic charges (nonpolarized) substituted for the in situ charges. These values were subtracted and tabulated for each anesthetic– protein complex. Further analyses of amino acid residue proximities, as well as atomic proximities that could be involved in hydrogen bonding, were performed using DSViewer 5.0 (Accelrys, San Diego, CA).
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RESULTS |
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TopAbstractIntroductionMETHODSRESULTSDISCUSSIONCONCLUSIONSREFERENCES |
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Each anesthetic binding site analyzed showed both significant polar and nonpolar character (Fig. 1A). The nonpolar interactions were provided by the proximity of several amino acids with nonpolar side chains. Both polar amino acids and water molecules in the binding sites accounted for the polar characteristics. A comparison of the partial atomic charges of the optimized anesthetic ligands in vacuo to those present when the anesthetics were within the binding sites showed clear polarization of the anesthetic molecules. For each anesthetic binding site, we tabulated the polarization of the anesthetic, the proximity and number of water molecules within 5 Å of the anesthetic (both water molecules included in the crystal structure and those added by the solvation algorithm), and the number of nonpolar and polar residues within 5 Å of the anesthetic. We graphed the extremes of the variance in electrostatic potential over the surface of the binding cavity. We also noted the potential for hydrogen bond formation as defined by a distance <2.5 Å between a hydrogen atom and a possible hydrogen bond acceptor. We chose to study interactions within a 5 Å radius because, whereas nonpolar noncovalent interactions (i.e., van der Waals and London dispersion forces) are weak beyond 3 Å, electrostatic interactions remain important, even assuming a protein dielectric constant of 5 (20). Lastly, it was clear that substituting the optimized in vacuo anesthetic charges onto the anesthetic while it was within the binding site made for a more energetically unfavorable complex by 1–2 kcal/mol. All calculations were performed at neutral pH.
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Dichloroethane Dehalogenase
There was one dichloroethane (DCE 600) within 2DHC. The binding site was formed by side chains from the polar residues GLU56, ASP124, HIS289, and the nonpolar residues TRP125, PHE128, PHE164, PHE172, TRP175, LEU179, PHE222, PRO223, VAL226, LEU262, and LEU263. One water (HOH485) was present around the DCE from the original crystal structure. The solvation algorithm added five additional waters within a 5 Å radius of the DCE. Together, these water and amino acid moieties induced significant asymmetry in the otherwise symmetric in vacuo charge distribution of the two chlorines and hydrogens (Fig. 1A). Despite this polarization, the overall geometry of the DCE from the in vacuo and in situ states was virtually identical (RMSD = 0.09 Å). There was a weak hydrogen bond between a chlorine atom of the DCE and the hydrogen on the adjacent TRP172 due to a H—Cl distance of 2.30 Å. There was also a hydrogen bond donation from the DCE to a nitrogen on TRP175 with an N—H distance of 2.09 Å, in addition to an added water due to an O—H distance of 2.18 Å. Lastly, the polarized state of the anesthetic was stabilized within the complex by 3.7 kcal/mol over the in vacuo charge distribution.
Bromoform–Luciferase Complex
There were two bromoforms within 1BA3. While one bromoform was bound very close to the protein surface, the ligand chosen for analysis (MBR 991) was the bromoform that was bound to an inner protein cavity. The binding site surrounding the bromoform was formed by side chains from the polar amino acids ARG218, THR251, TYR255, GLU311, SER314, ARG337, GLN338, and SER347, the nonpolar amino acids PHE227, PHE247, LEU286, and the backbone atoms of GLY228, ALA313, GLY315, GLY316, and GLY339. Three waters present around the bromoform were from the original crystal structure (HOH728, 750, 901). The solvation algorithm added an additional seven waters within a 5 Å radius of the bromoform. The polar moieties induced a polarization of the bromoform, causing significant asymmetry in the otherwise symmetric in vacuo charge distribution of the bromines (Fig. 1A). Despite this polarization, the overall geometry of the bromoforms from the in vacuo and in situ states were virtually identical (RMSD = 0.06 Å). The bromoform did show the possibility for weak hydrogen bond between a bromine atom and an added water due to an H—Br distance of 2.38 Å. Likewise, bromoform could act as a hydrogen bond donor as exemplified by an O—H distance with water (HOH570) of 2.44 Å. Lastly, the polarized state was stabilized within the complex by 1.38 kcal/mol over the in vacuo charge distribution.
Halothane–Albumin Complex
There were three halothanes within 1E7B. The halothane chosen for analysis (HLT 2003) was bound to an inner protein cavity that was also known to bind propofol in the propofol–albumin crystal structure 1E7A. The binding site surrounding halothane was formed by side chains from the polar amino acids ASN391, CYS392, CYS438, the nonpolar amino acids LEU387, ILE388, PHE395, PHE403, LEU407, ARG410, LEU430, VAL433, LEU453, and the backbone atoms of GLY431, GLY434, ALA449. One water (HOH9) from the original crystal structure was close to the halothane. The hydration algorithm added an additional five waters within a 5 Å radius of the halothane. The polar moieties induced significant asymmetry in the otherwise symmetric in vacuo charge distribution of the fluorines, and altered the partial atomic charges on the chlorine and bromine atoms (Fig. 1A). Despite this polarization, the overall geometry of the halothanes from the in vacuo and in situ states were very similar (RMSD = 0.11 Å). There was a possible hydrogen bond between the fluorine atom of the halothane and the hydrogen on an adjacent added water molecule due to an H-F distance of 2.14 Å. There was also a possible hydrogen bond between the acidic hydrogen on halothane and another added water due to an O—H distance of 2.3 Å. Lastly, the polarized state was stabilized within the complex by 0.7 kcal/mol over the in vacuo charge distribution.
Halothane–Cholesterol Oxidase Complex
There were two halothanes within the cholesterol oxidase–halothane complex. The halothane chosen for analysis (HAL509) was the ligand farthest away from the FAD reducing complex. The binding site surrounding the selected halothane was formed by side chains from the polar residues MET59, GLN75, MET325, THR342, TYR446, the nonpolar residues VAL77, PHE83, VAL217, ILE218, ALA363, LEU365, LEU375, the backbones of PRO76, PRO364, and PRO366, and a second halothane (HAL 508). One water (HOH991) present around the halothane was from the original crystal structure. The hydration algorithm added an additional two waters within a 5 Å radius of the halothane. The polar moieties also induced significant asymmetry in the otherwise symmetric in vacuo charge distribution of the fluorines, as well as altering the partial atomic charges on the chlorine and bromine (Fig. 1A). Despite this polarization, the overall geometry of the halothanes from the in vacuo and in situ states were very similar (RMSD = 0.09 Å). There were several possible hydrogen bonds between the fluorines of the halothane and surrounding structures: with HOH991 due to H-F distances of 2.45–2.49 Å, and with an added water due to an H-F distance of 2.48 Å. There was also a possible hydrogen bond between the acidic hydrogen of the halothane and an oxygen on the adjacent PRO364 due to an O—H distance of 2.44 Å. Lastly, the polarized state was stabilized within the complex by 2.89 kcal/mol over the in vacuo charge distribution.
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DISCUSSION |
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TopAbstractIntroductionMETHODSRESULTSDISCUSSIONCONCLUSIONSREFERENCES |
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To understand the physicochemical nature of anesthetic binding sites within proteins, many studies have inferred the possible characteristics of an "average" anesthetic binding site. Clearly, the Meyer–Overton correlation still holds true for most anesthetic compounds, and so the average anesthetic binding site must have some nonpolar character. The exceptions to the Meyer–Overton correlation demonstrate a dependence on polar characteristics within the series of transitional compounds; therefore, there must be some polar character within the anesthetic binding site (6,10). This was first argued on the basis of correlations with solvents of differing polarities, where it was shown that the relatively polar solvent n-octanol gave an improved correlation over n-alkanes and olive oil (21). Further work by Johansson et al. (22) correlated potency within a series of solvents that simulated various amino acid side chain environments and found that a methionine-like solvent best mimics an anesthetic binding site.
In this study, we sought to describe general binding motifs between anesthetics and the various chemical moieties of proteins and water within four well-described anesthetic–protein complexes. Volatile anesthetics are of a variety of shapes and sizes. While most are relatively nonpolar and all are uncharged, some anesthetics have partial polar character. We have shown that the interaction of volatile anesthetics with proteins involves a binding site characterized by several common nonpolar and polar types of interactions. In fact, the binding pocket is amphiphilic in nature, incorporating anesthetic interactions with both polar and nonpolar amino acid side chains as well as with water.
In all four examples studied here, Coulombic and van der Waals interactions within the binding sites were augmented by interactions in which the binding sites induced polarization of the anesthetic ligands. This result is consistent with earlier studies that correlated anesthetic potency with the charge-induced polarization of noble gases in a polar environment (23).
The hydrogen bonds noted in each complex are of the weak type described by Sandorfy (24). In fact, he concluded that weak H-bonds and van der Waals contacts are the prime mediators of reversible anesthetic–protein interactions. These weak H-bonds are characterized primarily by the distance between the hydrogen bond acceptor and the donated hydrogen. They do not necessarily meet the more stringent criteria of strong hydrogen bonds suggested by the combination of smaller donor–acceptor distances, specific donor–acceptor hydrogen-bond angles, or significant donor–acceptor electron density overlaps. Several other studies have implicated weak hydrogen bond interactions within anesthetic binding sites (25). Abraham et al. (25) suggested: "general anesthetic target sites in animals must have, in addition to their overall hydrophobicity, a polar component which is a relatively poor hydrogen bond donor, but which can accept a hydrogen bond about as well as water." This finding is consistent with our present results in which we observe the possibility of hydrogen bond formation between the anesthetic molecules and both water and amino acids. The anesthetic can be seen to function as both a hydrogen bond donor, and in the case of the halogen atoms, an acceptor as well. A more recent study (26) pointed out that, because of their negative partial atomic charges, halogen atoms bound to carbon can act as hydrogen bond acceptors. However, they may be weak when compared to those involving water.
We expected, and found, water molecules within the binding sites. These water molecules either were in the original crystal structure or were added by the solvation algorithm used. There were several reasons that we expected water molecules to surround the anesthetic ligands: First, in three of the four structures we studied, anesthetics were not the natural ligand. Therefore, it is reasonable that the anesthetics did not fit the binding site perfectly and there was additional space for water. Second, the general binding of an anesthetic molecule is strongly entropically favored by displacing existing water molecules from a binding site (27,28). There is a considerable entropic penalty to pay for limiting the translational and rotational motions of a bound anesthetic molecule. This penalty can be compensated for by "liberating" several water molecules from the binding site into bulk solution. Third, there is much structural evidence for water molecules within internal cavities in proteins (28–31). The ability of water molecules to be selectively displaced from a site allows the site to accept ligands of different sizes and volumes (27,28). We suggest that this property is essential in that binding sites within a limited number of receptors must accept anesthetics that range in size from xenon to isoflurane (32). The presence of water allows for a significant amount of binding "promiscuity" with regards to ligand size, shape, and polarity.
Recent analyses (33) of several halogenated volatile anesthetics have produced similar results concerning the necessary combination of both "bulk" properties and electrostatic interactions to adequately account for anesthetic binding and potency. In particular, Sewell and Sear have used comparative molecular field analysis to study the chemical characteristics of a large series of halogenated volatile anesthetics and have constructed an anesthetic pharmacophore that has both polar and nonpolar characteristics. This method is based solely on the analysis of ligands without reference to any type of specific protein binding site, yet reveals similar physicochemical characteristics for anesthetic binding.
Recent work (12,13) on constructing molecular models of anesthetic binding sites within the transmembrane domains of LGICs is consistent with the motif of an amphiphilic and promiscuous binding site. Specifically, using modern techniques of bioinformatics, computational chemistry, and molecular modeling, we have built models of the transmembrane domain within GABAAR 1 and GlyR that reasonably account for a large body of physicochemical and experimental data that characterize anesthetic binding sites. Most notably, a cavity within the center of a four--helix bundle demonstrates the proximity of amino acid residues involved in the effects of anesthetics on these ion channels, thereby forming a plausible anesthetic binding site. This binding site is also amphiphilic in physicochemical character and is large enough to contain an anesthetic and some water molecules (Fig. 1B).
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CONCLUSIONS |
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TopAbstractIntroductionMETHODSRESULTSDISCUSSIONCONCLUSIONSREFERENCES |
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Molecular modeling and analysis reveals that anesthetic binding sites within several well-characterized anesthetic–protein complexes are amphiphilic, and not just hydrophobic. Such interactions involve weak hydrogen bonds, van der Waals interactions, and other weak polar interactions that many previous studies have implicated as necessary for reversible anesthetic binding. In particular, such an amphiphilic binding site actually induces significant polarization of the anesthetic itself, thereby contributing what may be a significant part of the anesthetic binding energy. These general binding motifs, when applied to ion channel proteins that may be responsible for anesthetic effects, may help to explain the relative potencies of the transitional compounds as well as those that obey the Meyer–Overton correlation. This information may provide an understanding of anesthetic action at the atomic level.
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ACKNOWLEDGMENTS |
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The authors thank Peter Brick, Imperial College, London, for providing the coordinates of the halothane–cholesterol oxidase complex.
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Footnotes |
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1 Bertaccini E, Trudell JR, Brick P, et al. The interaction of halothane with the binding site of a functional protein, cholesterol oxidase. Anesthesiology 1998;89:A97.
Accepted for publication October 19, 2006.
Supported by the Stanford University Department of Anesthesia; the United States Department of Veterans Affairs; and the National Institutes of Health.
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