Force-Field Simulations of a Hydrated Lanreotide-Based Derivative: Hydration, Dynamics, and Numerical Evidence of Self-Assembly in Dimers.

Florian Pinzan,Franck Artzner,Aziz Ghoufi

doi:10.1021/acsomega.0c03852

Abstract

Recently, self-organization of the cyclic octapeptide lanreotide and lanreotide-based derivatives in a nanotube to from a dimer structure has been experimentally evidenced. While the nature of the interactions between both monomers has been strongly investigated no molecular details of the hydration of the monomer and the formation of the dimer have been provided. Using molecular dynamics simulations, this work focuses on the structure, hydration, and dynamics of water and an analog of lanreotide. To do so, several models of monomers based on different schemes of partial charges and electrostatic interaction calculations are considered. By comparison with the experiments, we show that the model based on the combination of the AMBER force-field, CHELPG charge calculation, Ewald sum is the most relevant. Additionally, by mapping the interfacial hydration of the lanreotide monomer we evidence a heterogeneous surface in terms of hydrophilicity involving heterogeneous hydration. Furthermore, we show a slowdown in the translational dynamics of water molecules located close to the lanreotide surface. We also provide the molecular details of the self-assembly in the dimer in terms of structure, hydration, and energy.

Highlights

Self-organization is ruled by specific associations of molecules involving weak interactions such as hydrogen-bonding, hydrophobic, electrostatic, van der Waals, and π−π interactions[1−5] and provides different natural structures such as membranes, biological nanotubes, amyloid-beta protofibrils, or actin filaments
This packing exhibits as many as four hierarchical levels of organization, which, from the lowest to the highest, are[7,11,12,14] (1) dimers of peptides essentially stabilized by hydrophobic effects and aromatic side chain interactions; (2) amyloid filaments generated by the packing of peptide dimers through an intermolecular antiparallel β-sheet network between the peptide backbones; (3) nanotubes generated by the lateral packing of 26 filaments, in which the H-bond network lies flat on the nanotube surface; and (4) the packing of the nanotubes in a hexagonal lattice
Valeŕ y et al, showed that three parameters are essential for the formation of lanreotide nanotubes: (i) the specificity of two of the three aromatic side chains, (ii) the spatial arrangement of the hydrophilic and hydrophobic residues, and (iii) the aromatic side chain in the β-turn of the molecule.[14]

Summary

Introduction

Self-organization is ruled by specific associations of molecules involving weak interactions such as hydrogen-bonding, hydrophobic, electrostatic, van der Waals, and π−π interactions[1−5] and provides different natural structures such as membranes, biological nanotubes, amyloid-beta protofibrils, or actin filaments Nowadays, numerous applications such as drug delivery are based on the self-organization,[1,6] and it is fundamental to well understand the physical processes ruling the self-assembly of these molecules.[6,7] In the last few decades, many experimental and numerical works have been reported on the mechanism of self-assembly at the molecular scale and a connection between the geometrical complementarity, the chemical components and the weak interactions has been established. The experimental studies have been focused on the peptide−peptide interactions to elucidate the molecular mechanism controlling the selfassembly; the solvation/hydration state of the Received: August 11, 2020 Accepted: September 10, 2020 Published: September 24, 2020

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