Why a diaminopyrrolic tripodal receptor binds mannosides in acetonitrile but not in water?

Abstract

Intermolecular interactions involving carbohydrates and their natural receptors play important roles in several biological processes. The development of synthetic receptors is very useful to study these recognition processes. Recently, it was synthetized a diaminopyrrolic tripodal receptor that is selective for mannosides, which are obtained from mannose, a sugar with significant relevance in living systems. However, this receptor is significantly more active in acetonitrile than in water. In this work, we performed several molecular dynamics and constant-pH molecular dynamics simulations in acetonitrile and water to evaluate the conformational space of the receptor and to understand the molecular detail of the receptor-mannoside interaction. The protonation states sampled by the receptor show that the positive charges are always as distant as possible in order to avoid large intramolecular repulsions. Moreover, the conformational space of the receptor is very similar in water above pH 4.0 and in acetonitrile. From the simulations with the mannoside, we observe that the interactions are more specific in acetonitrile (mainly hydrogen bonds) than in water (mainly hydrophobic). Our results suggest that the readiness of the receptor to bind mannoside is not significantly affected in water (above pH 4.0). Probably, the hydrogen bond network that is formed in acetonitrile (which is weaker in water) is the main reason for the higher activity in this solvent. This work also presents a new implementation of the stochastic titration constant-pH molecular dynamics method to a synthetic receptor of sugars and attests its ability to describe the protonation/conformation coupling in these molecules.

Keywords: conformational analysis; constant-pH MD; mannose; multivalent glycosystems; pH; synthetic receptor.

Figure 1

Octyl α-D-mannoside (mannoside) and diaminopyrrolic tripodal receptor molecules. 2D and 3D representations are shown. In 3D, all hydrogen atoms were omitted for clarity, and titrable amino groups are shown in spheres with first generation in dark blue and second in light blue.

Figure 2

Full titration curve of the receptor (a) and the correspondent percentage of protonation in each generation (b).

Figure 3

Diagram representing the population of all microstates at each number of titrable protons (n) present in the molecule.

Figure 4

Radius of gyration (R_g) histograms for the receptor in water at pH 1.0, 3.0, 6.0, 10.0 and in ACN. The R_g curves at the pH values not shown are well behaved and respect the observed trend.

Figure 5

Free energy profiles for the receptor at pH 1.0 (a), 6.0 (b), 10.0 (c) and ACN (d) using RMSD and R_g as structural coordinates. The RMSD was calculated using the NMR derived structure as reference.

Figure 6

Schematic representation of the receptor arms positions. Pyrrolic nitrogen atoms positions relative to the phenyl ring in 900 conformations at pH 1.0, 6.0, 10.0 and in ACN.

Figure 7

Histogram of the hydrogen bonds between receptor and mannoside in ACN and water (at different protonation states).

Figure 8

Distance histograms between the center of mass of the last 4 atoms of the carbon chain of the mannoside and the 6 atoms of the phenyl ring in the receptor. Calculations were done in ACN and water (at different protonation states).

Figure 9

Typical conformations in water and ACN. The selected conformations have 6 hydrogen bonds in ACN and 1 in water.