Water–Tryptophan Interactions: Lone‐pair⋅⋅⋅π or O−H⋅⋅⋅π? Molecular Dynamics Simulations of β‐Galactosidase Suggest that Both Modes Can Co‐exist

Abstract

In proteins, the indole side chain of tryptophan can interact with water molecules either in-plane, forming hydrogen bonds, or out-of-plane, with the water molecule contacting the aromatic π face. The latter interaction can be either of the lone pair⋅⋅⋅π (lp⋅⋅⋅π) type or corresponds to the O-H⋅⋅⋅π binding mode, an ambiguity that X-ray structures usually do not resolve. Here, we report molecular dynamics (MD) simulations of a solvated β-galactosidase monomer, which illustrate how a water molecule located at the π face of an indole side chain of tryptophan can adapt to the position of proximate residues and "select" its binding mode. In one such site, the water molecule is predicted to rapidly oscillate between the O-H⋅⋅⋅π and lp⋅⋅⋅π binding modes, thus gaining entropic advantage. Our MD simulations provide support for the role of lp⋅⋅⋅π interactions in the stabilization of protein structures.

Insight into glycosphingolipid crypticity: Crystal structure of the anti-tumor antibody 14F7 and recognition of NeuGc GM3 ganglioside

“…In the case of 14F7, Wat1 is already present in the protein apo-structure (PDB ID: 6FFJ 9 ). A thorough analysis of water–tryptophan interactions indicates that the six-membered ring of the indole side chain favors π-OH interaction, while the five-membered pyrrole ring favors π-lone pair interaction 53 . The latter appears to be the case for Wat1, thus positioning it as an H-bond donor for the N -glycolyl group of NeuGc GM3.…”

Key role of a structural water molecule for the specificity of 14F7—An antitumor antibody targeting the NeuGc GM3 ganglioside

“…2018 ) ( Figure 2 A ). A thorough analysis of water–tryptophan interactions indicates that the six-membered ring of the indole side chain favors π-OH interaction, whereas the five-membered pyrrole ring favors π-lone pair interaction ( Durec et al. 2018 ).…”

Molecular design opportunities presented by solvent‐exposed regions of target proteins

“…As described above, structurally conserved bound water molecules can also play a critical role. In computer‐assisted rational drug design, particular emphasis should be placed on so‐called unconventional interactions between water and heterocyclic nitrogens, as exemplified by lone‐pair‐π (lp‐π) interactions . It should be pointed out that the water is considered poorly understood, consequently, there are still some challenges in the rational treatment of structured water molecules in drug design.…”