Advanced Molecular Dynamics Approaches to Model a Tertiary Complex APRIL/TACI with Long Glycosaminoglycans.

Mateusz Marcisz,Bertrand Huard,Martyna Maszota-Zieleniak,Sergey A Samsonov

doi:10.3390/biom11091349

Abstract

Glycosaminoglycans (GAGs) are linear anionic periodic polysaccharides participating in a number of biologically relevant processes in the extracellular matrix via interactions with their protein targets. Due to their periodicity, conformational flexibility, pseudo-symmetry of the sulfation pattern, and the key role of electrostatics, these molecules are challenging for both experimental and theoretical approaches. In particular, conventional molecular docking applied for GAGs longer than 10-mer experiences severe difficulties. In this work, for the first time, 24- and 48-meric GAGs were docked using all-atomic repulsive-scaling Hamiltonian replica exchange molecular dynamics (RS-REMD), a novel methodology based on replicas with van der Waals radii of interacting molecules being scaled. This approach performed well for proteins complexed with oligomeric GAGs and is independent of their length, which distinguishes it from other molecular docking approaches. We built a model of long GAGs in complex with a proliferation-inducing ligand (APRIL) prebound to its receptors, the B cell maturation antigen and the transmembrane activator and calcium modulator and cyclophilin ligand interactor (TACI). Furthermore, the prediction power of the RS-REMD for this tertiary complex was evaluated. We conclude that the TACI–GAG interaction could be potentially amplified by TACI’s binding to APRIL. RS-REMD outperformed Autodock3, the docking program previously proven the best for short GAGs.

Highlights

Despite the recent advances in molecular docking of glycosaminoglycan (GAG)oligosaccharides, it still remains a challenge to dock longer GAGs [1]
It was reported that the C-terminus spatially close to the N-terminus, together with several arginine residues on the side of the protein, contribute to GAG binding [13]. While this binding of GAGs to a proliferation-inducing ligand (APRIL) is believed to be a facilitation agent for its binding to receptors, B cell maturation antigen (BCMA) and TACI [30,31], it has been shown that BCMA does not bind to HSPG
Following X-ray experimental structures from PDB were used in this work: 1XU2 and 1XU1 [36]

Summary

Introduction

Oligosaccharides, it still remains a challenge to dock longer GAGs [1]. The main reason for this is the physical–chemical nature of GAGs. Increasing pairwise van der Waals radii as it is done in RS-REMD (while not affecting other types of interactions for the system) can be helpful to overcome this challenge In this way, the mentioned method allows for a robust and extensive search for the proper binding poses on the complete protein surface, allowing, at the same time, for full flexibility of the docked molecule and the receptor side chains. It was reported that the C-terminus spatially close to the N-terminus, together with several arginine residues on the side of the protein, contribute to GAG binding [13] While this binding of GAGs to APRIL is believed to be a facilitation agent for its binding to receptors, BCMA and TACI [30,31], it has been shown that BCMA does not bind to HSPG (heparan sulfate proteoglycan) [32,33]. Our results contribute to the general knowledge about GAG-specific computational approaches

Structures

Molecular Docking

Molecular Dynamics

Binding Free Energy Calculations

Docking Heparin dp24 to APRIL–BCMA and APRIL–TACI Complexes Using Autodock3

Docking Heparin dp24 and dp48 to APRIL–BCMA and APRIL–TACI Complexes