The Geometry of Hydrogen Bonds

It is important to be aware of this in considering any particular protein-ligand structure. Indeed, there is a good case for forcing satisfaction of the weak criteria for classic hydrogen bond donors and acceptors in structure refinement and/or modeling studies of proteins, although this is not routinely done. 

Statistical analyses of both proteins and small molecules reveal fhat hydrogen bond stereochemistry is influenced by two major factors the electronic configuration of the acceptors and the steric accessibility of the acceptors and donors. Considering the most common hydrogen bond in biological chemistry, there is a distinct preference for N-H - O=C bonds to form in the O=C-RR plane and in the directions of the conventionally viewed sp lone pairs [13], wifh the proton lying within 30 of the plane and at 30-60 ° to the O=C axis in the majority of cases. 

Note fhat in relation to the simple model of a hydrogen bond as an electrostatic dipole-dipole interaction, which is embodied in most modeling software, fhe D-H group does not lie along fhe dipole but points to the lone pairs. Note also fhat there is no absolute requirement for linearity of the acceptor-proton-donor system. 

The effect of electronic configuration of the acceptor is particularly apparent in the contrast of Ser/Thr and Tyr hydroxyl groups the phenolic hydroxyl of tyrosine has a preference for near-plane position for donors and/or acceptors, as its sp hybridization leaves the lone pair electrons in the plane of the ring [15, 16], whereas serine and threonine hydroxyls have sp hybridization with two acceptor and one donor position at 120° spacing (the donating proton is usually trans to the carbon three covalent bonds away). The observed spatial distributions for the principal amino acid donor and acceptor groups are illustrated schematically in Fig. 6.1. 

The significance of tliese observations was not immediately appreciated, but a few further important examples, including the observation of several amino hydrogen bonds to the ring of the phosphotyrosine in its recognition by SH2 domains, as shown in Fig. 6.2 [20], and a later review by Perutz [21] stimulated both structural analyses and dieoretical studies of D-H - -Tt-acceptor systems in proteins [22, 23]. It has been shown that such bonds are relatively rare compared to the usual 

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Many studies have been made of the geometry of hydrogen bonds, and the evidence shows that in most (though not all) cases the hydrogen is on or near the... 

Compare the flexibility of the geometry of hydrogen-bonding to the non-bonding electron-pairs of neutral oxygen elicited by the demands of crystal forces (Donohue, 1968)... 

H.A. Staab, T. Saupe, Proton sponges and the geometry of hydrogen bonds aromatic nitrogen bases with exceptional basicities. Angew. Chem. Int. Ed. Engl. 27, 865-1008 (1988)... 

The geometry of the hydrogen bond can be described by the parameters R, n, r2, and 0, as shown in Fig. 11.2.1. Numerous experimental studies have established the following generalizations about the geometry of hydrogen bonds ... 

The problem of transference from the hydrogen bonds in the crystal to those in a biological process is not different, in principle, from the transference of molecular structural information determined by crystal structure analysis to the interpretation of the mechanism of a chemical reaction. In Chapter 4, we discuss the differences between the geometry of hydrogen bonds in crystals and in the free molecule models that are necessarily used by the theoretical methods. 

Pedersen B (1974) The geometry of hydrogen bonds from donor water molecules. Acta Cryst B30 289—291... 

Jeffrey GA, Maluszynska H (1986) A survey of the geometry of hydrogen bonding in barbiturates, purines and pyrimidines. J Molec Struct 147 127-142... 

The geometries of hydrogen bonded trimers and tetramers in solid 3,5-sub-stituted pyrazoles (Fig. 6) have been studied from consideration of both 15N chemical shift tensors and dipolar interactions involving 15N [122]. 

Schulz-Dobrick M et al (2005) Determining the geometry of hydrogen bonds in solids with picometer accuracy by quantum chemical calculations and NMR spectroscopy. 

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