Antiperiplanar Lone Pair Hypothesis Research Articles

Intrinsic dynamic behavior of enzyme:substrate complexes govern the catalytic action of \u03b2-galactosidases across clan GH-A

The conformational itineraries taken by carbohydrate residues in the catalytic subsite of retaining glycoside hydrolases (GHs), harness the link between substrate conformation and reactivity. GHs’ active sites may be described as a combination of subsites dedicated to the binding of individual sugar residues and to catalysis. The three-dimensional structure of GH:carbohydrate complexes has demonstrated that carbohydrate ring conformation changes in an ordered manner during catalysis. Here we demonstrate in silico that a link exists between subsite binding dynamics and substrate specificity for β-galactosidases from clan GH-A families GH1, GH2, GH35, GH42 and GH59. Different oligosaccharides were docked in the active site of reference β-galactosidase structures using Vina-Carb. Subsequent molecular dynamics (MD) simulations revealed that these enzymes favor a high degree of flexibility and ring distortion of the substrate the lytic subsite −1. Although the β-galactosidase families examined are structurally and mechanistically related, distinct patterns of ring distortion were unveiled for the different families. For β-galactosidases, three different family-dependent reaction itineraries (1S3 → 4H3‡ → 4C1, 1,4B → 4H3/ 4E‡ → 4C1, and 1S5 → 4E/ 4H5‡ → 4C1) were identified, all compatible with the antiperiplanar lone pair hypothesis (ALPH) for the hydrolysis of β-glycosides. This comparative study reveals the fuzzy character of the changes in carbohydrate ring geometry prior to carbohydrate hydrolysis.

Salts of hexamethylenetetramine with organic acids: Enhanced anomeric interactions with a lowering of molecular symmetry revealed by crystal structures

The hexamethylenetetramine (HMT) framework displays interesting stereoelectronic interactions of the anomeric type. In the highly symmetrical parent system, the nitrogen centres act as both donors and acceptors. Protonation lowers symmetry and also leads to an enhancement of the anomeric interaction around the protonated centre. X-ray diffraction crystal structures of four derivatives of HMT – with succinic, (DL)-malic, phthalic and 4-hydroxybenzoic acids – reveal significant trends. (The first three form well-defined salts, 4-hydroxybenzoic acid forming a co-crystalline compound.) Each molecular structure is essentially characterised by a major anomeric interaction involving the protonated centre as acceptor. In two cases (succinic and 4-hydroxybenzoic), secondary protonation leads to a weaker anomeric interaction site that apparently competes with the dominant one. Bond length changes indicate that the anomeric interaction decreases as malic>phthalic>succinic>4-hydroxybenzoic, which correlates with the degree of proton transfer to the nitrogen centre. Along with other bond length and angle changes, the results offer insight into the applicability of the antiperiplanar lone pair hypothesis (ALPH) in a rigid system.

An encaged σ∗ orbital in 3-methoxy-2,4,10-trioxaadamantane. Preferred exo-anomeric effect as revealed by the crystal structure

In the titled tricyclic orthocarbonate derivative, the three endocyclic C–O bonds are longer than the exocyclic C–O bond (∼1.40Å vs. ∼1.37Å). This indicates an anomeric-type interaction between the two electron lone pairs on the exocyclic oxygen atom and the antibonding orbitals of the two antiperiplanar endocyclic C–O bonds. The remaining endocyclic C–O bond – marginally shorter than the other two – apparently adds to this effect. Intriguingly, the antibonding orbital of the exocyclic C–O bond extends into the interior of the adamantyl cage, and is stereoelectronically prevented from overlapping with any of the six adjacent lone pairs. The results also seem to indicate a preference for interaction between a single donor oxygen atom and multiple acceptor antibonding orbitals rather than vice versa. The results add insightfully to the substantial body of evidence favouring the antiperiplanar lone pair hypothesis (ALPH).

ChemInform Abstract: Cyclization of Hydroxyenol Ethers into Spiroacetals. Evidence for the Position of the Transition State and Its Implication on the Stereoelectronic Effects in Acetal Formation.

Acid-catalyzed cyclizations under thermodynamically and kinetically controlled conditions of the hydroxyenol ethers 18–21 are reported. Thermodynamically controlled cyclizations of 18, 19 and 21 produced only the more stable corresponding spiroacetals 22 and 27. Thermodynamically controlled cyclization of compound 20 produced a 1:1 mixture of non-epimerisable spiroacetals 24 and 26. On the other hand, kinetically controlled cyclizations of the same four hydroxyenol ethers produced, along with the more stable spiroacetals mentioned above, the less stable spiroacetals 23, 25, and 28. These results show that the kinetically controlled cyclization takes place via an early transition state which produces a mixture of the less stable and the more stable isomers. These results are explained by an early transition state taking into account the principle of stereoelectronic control while following the antiperiplanar lone-pair hypothesis (Burgi-Dunitz angle of attack of a nucleophile on a π system).

Mechanism of Cellulose Hydrolysis by Inverting GH8 Endoglucanases: A QM/MM Metadynamics Study

A detailed understanding of the catalytic strategy of cellulases is key to finding alternative ways to hydrolyze cellulose to mono-, di-, and oligosaccharides. Endoglucanases from glycoside hydrolase family 8 (GH8) catalyze the hydrolysis of beta-1,4-glycosidic bonds in cellulose by an inverting mechanism believed to involve a oxacarbenium ion-like transition state (TS) with a boat-type conformation of the glucosyl unit in subsite -1. In this work, hydrolysis by Clostridium thermocellum endo-1,4-glucanase A was computationally simulated with quantum mechanics/molecular mechanics metadynamics based on density functional theory. Our calculations show that the glucosyl residue in subsite -1 in the Michaelis complex is in a distorted 2SO/2,5B ring conformation, agreeing well with its crystal structure. In addition, our simulations capture the cationic oxacarbenium ion-like character of the TS with a partially formed double bond between the ring oxygen and C5' carbon atoms. They also provide previously unknown structural information of important states along the reaction pathway. The simulations clearly show for the first time in GH8 members that the TS features a boat-type conformation of the glucosyl unit in subsite -1. The overall catalytic mechanism follows a DN*AN-like mechanism and a beta-2SO-->2,5B [TS]-->alpha-5S1 conformational itinerary along the reaction coordinate, consistent with the anti-periplanar lone pair hypothesis. Because of the structural similarities and sequence homology among all GH8 members, our results can be extended to all GH8 cellulases, xylanases, and other endoglucanases. In addition, we provide evidence supporting the role of Asp278 as the catalytic proton acceptor (general base) for GH8a subfamily members.

Some recent developments in stereoelectronic theory. Reevaluations of ALPH and the reverse anomeric effect

A critique of objections to the 'antiperiplanar lone pair hypothesis' (ALPH) and the 'reverse anomeric effect' (RAE) is presented. Whilst early fears that ALPH is incompatible with the Curtin-Hammett principle (CHP) were apparently unfounded, objections to ALPH based on the reactions of cyclic hemiorthoesters and amidinium salts are debatable. (The unreactivity of Kirby's bicyclic bridgehead acetal supports ALPH convincingly.) Objections to RAE were based on its apparent incompatibility with ALPH, studies on several models indicating (dubiously) the existence of a weak anomeric effect rather than RAE. However, this may well suggest that a normal anomeric effect is being offset by RAE. This apparently indicates different bases for the ground state and kinetic anomeric effects: the classical 'electrostatic gauche repulsive interaction' (EGRI) and the 'orbital interaction' (OI) respectively. The evidence against free oxocarbenium ions, but favouring the ion pair and the 'exploded transition state' (ETS) models apparently raises the question 'Whither ALPH?'. A rigorous application of the CHP to the stereochemistry of displacements at glycosyl anomeric centres, indicates that the alpha anomers react retentively via ion pairs, whereas the beta anomers react with inversion via the ETS. (A substantial reassessment of the 'in situ anomerisation technique' is also indicated.)

Inapplicability of the Antiperiplanar Lone Pair Hypothesis to C-P Bond Breaking and Formation in Some S-C-P(+) Systems.

Both C(2)-P bond breaking and formation in the S-C-P(+) system do not occur according to the antiperiplanar lone pair hypothesis. Experiments using 2-phosphonio derivatives of 5-tert-butyl-1,3-dithiane and cis-4,6-dimethyl-1,3-dithiane are against the participation of higher-energy boat conformers as reactive intermediates. The results obtained support a possibility of conformational adjustment in the course of the reaction. Stereoelectronic control of the C(2)-P bond breaking and formation results from interplay of several factors. The role of the n(S)-sigma(C(2))(-)(P) and sigma(C(4,6))(-)(S)-sigma(C(2))(-)(P) hyperconjugation, as well as of the repulsive interactions between lone electron pairs pi(S) of endocyclic sulfur atoms and pi-electrons of the phenyl ring(s) connected with phosphorus, is discussed.

The chemistry of N-pentenyl glycosides: Synthetic, theoretical, and mechanistic ramifications

Abstract

Concerning the antiperiplanar lone pair hypothesis: oxidative hydrolysis of conformationally restrained 4-pentenyl glycosides

ADVERTISEMENT RETURN TO ISSUEPREVArticleNEXTConcerning the antiperiplanar lone pair hypothesis: oxidative hydrolysis of conformationally restrained 4-pentenyl glycosidesA. J. Ratcliffe, David R. Mootoo, C. Webster Andrews, and Bert Fraser-ReidCite this: J. Am. Chem. Soc. 1989, 111, 19, 7661–7662Publication Date (Print):September 1, 1989Publication History Published online1 May 2002Published inissue 1 September 1989https://doi.org/10.1021/ja00201a082RIGHTS & PERMISSIONSArticle Views250Altmetric-Citations36LEARN ABOUT THESE METRICSArticle Views are the COUNTER-compliant sum of full text article downloads since November 2008 (both PDF and HTML) across all institutions and individuals. These metrics are regularly updated to reflect usage leading up to the last few days.Citations are the number of other articles citing this article, calculated by Crossref and updated daily. Find more information about Crossref citation counts.The Altmetric Attention Score is a quantitative measure of the attention that a research article has received online. Clicking on the donut icon will load a page at altmetric.com with additional details about the score and the social media presence for the given article. Find more information on the Altmetric Attention Score and how the score is calculated. Share Add toView InAdd Full Text with ReferenceAdd Description ExportRISCitationCitation and abstractCitation and referencesMore Options Share onFacebookTwitterWechatLinked InReddit PDF (278 KB) Get e-Alerts Get e-Alerts

ChemInform Abstract: The Principle of Least Nuclear Motion and the Theory of Stereoelectronic Control

Publisher Summary This chapter discusses that the picture of an antiperiplanar lone pair of electrons driving off a leaving group had occurred intermittently in the literature at least as early as 1963; it is largely the initial work of Deslongchamp's group thatpresented a systematic body of work, which demanded explanation. It explores that antiperiplanar lone pair hypothesis (ALPH) requires no exceptions, whereas the explanation provided by the principle of least nuclear motion also accommodates the exceptions. Perhaps the best evidence that ALPH is too fundamental is the confusion that results when ALPH is taken as an axiom. The chapter discusses that such confusion can be illustrated by the multiplicity of otherwise unsubstantiated conformational changes required during the action of various enzymes, the successful rationalization of inadequate or incorrect data, and the calling into question of perfectly sound data, which happen not to fit an extension of the theory.

On the antiperiplanar lone pair hypothesis and its application to catalysis by glycosidases.

The idea that sp3 lone pairs of electrons on a heteroatom direct the departure of a leaving group from an adjacent tetrahedral carbon centre is shown to be untenable as a general principle, and the permissive evidence in favour of it to be accounted for by the principle of least nuclear motion. The application of the idea to the majority of glycopyranosidases, which work by a double-displacement mechanism, is shown to require implausible contortions of the pyranose ring.

Failure of the antiperiplanar lone pair hypothesis in glycoside hydrolysis. Synthesis, conformation, and hydrolysis of α-D-xylopyranosyl-and α-D-glucopyranosyl-pyridinium salts

(1) Two series of crystalline α-D-xylopyranosyl-and α-D-glucopyranosyl-pyridinium bromides have been made, by reaction of the acetylated α-bromides with the pyridines in an aprotic solvent in the presence of bromide ion, followed by deacetylation with aqueous HBr at room temperature. (2) 200 MHz 1H N.m.r. spectra in D2O of representatives of each series show the xylo-compounds to adopt the 1C4 conformation, and the gluco-compounds the 1S3 conformation. (3) The hydrolyses of α-D-xylopyranosyl- and α-D-glucopyranosyl-3-bromopyridinium ions in 1.0M-NaCIO4 at 25.0 °C are described by kobs/s–1=4.7 × 10–8+1.4 × 10–18/[H+] and kobs/s–1=2 × 10–7+1.4 × 10–17/[H+], respectively. (4) The products of pH-independent hydrolysis of the foregoing ions are the sugars and 3-bromopyridine, whereas at pH 12, 10% of both reactions proceed by attack on the pyridine ring: attack on the sugar yields glucose and 1,6-anhydroglucopyranose, but no xylose. (5) The pH-independent hydrolyses display strongly positive entropies of activation: at 25.0 °C, those of five xylo-compounds give a βlg value of –1.27 ± 0.06, and those of four gluco-compounds one of –1.06 ± 0.12. (6) Arguments are presented, in the light of the low α:β rate ratios for both xylo and gluco pyridinium salts (8–23 and 80, respectively, at 25 °C), that departure of a pyridine from C(1) of an aldopyranose ring does not require a conformation in which the leaving group is antiperiplanar to a lone pair of electrons on O(5). (7) The antiperiplanar lone pair hypothesis is shown to be a special case of the principle of least nuclear motion, which is known not to apply to reactions with very product-(or reactant-) like transition states.