Repulsive Scaling Replica Exchange Molecular Dynamics in Modeling Protein-Glycosaminoglycan Complexes.

Glycosaminoglycans are long linear periodic anionic polysaccharides consisting of disaccharide units exhibiting different sulfation patterns forming a highly heterogeneous group of molecules. Due to their flexibility, length, high charge, and periodicity, they are challenging for computational approaches. Despite their biological significance in terms of the important role in various diseases (e.g., Alzheimer, cancer, SARS-CoV-2) and proper cell functioning (e.g., proliferation, maturation), there is a lack of effective molecular docking tools designed specifically for glycosaminoglycans due to their challenging physical-chemical nature. In this chapter we present protocols for the Repulsive Scaling Replica Exchange Molecular Dynamics (RS-REMD) methods to dock glycosaminoglycans with both implicit and explicit solvent models implemented. This novel molecular dynamics-based replica exchange technique should help to elevate our current knowledge on the complexes and interactions between glycosaminoglycans and their protein receptors.

Explicit solvent repulsive scaling replica exchange molecular dynamics (RS-REMD) in molecular modeling of protein-glycosaminoglycan complexes.

Glycosaminoglcyans (GAGs), linear anionic periodic polysaccharides, are crucial for many biologically relevant functions in the extracellular matrix. By interacting with proteins GAGs mediate processes such as cancer development, cell proliferation and the onset of neurodegenerative diseases. Despite this eminent importance of GAGs, they still represent a limited focus for the computational community in comparison to other classes of biomolecules. Therefore, there is a lack of modeling tools designed specifically for docking GAGs. One has to rely on existing docking software developed mostly for small drug molecules substantially differing from GAGs in their basic physico-chemical properties. In this study, we present an updated protocol for docking GAGs based on the Repulsive Scaling Replica Exchange Molecular Dynamics (RS-REMD) that includes explicit solvent description. The use of this water model improved docking performance both in terms of its accuracy and speed. This method represents a significant computational progress in GAG-related research.

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

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.

Further analyses of APRIL/APRIL-receptor/glycosaminoglycan interactions by biochemical assays linked to computational studies.

A proliferation-inducing ligand (APRIL) is a member of the tumor necrosis factor superfamily. APRIL is quite unique in this superfamily for at least for two reasons: (i) it binds to glycosaminoglycans (GAGs) via its positively charged N-terminus; (ii) one of its signaling receptor, the transmembrane activator and CAML interactor (TACI), was also reported to bind GAGs. Here, as provided by biochemical evidences with the use of an APRIL deletion mutant linked to computational studies, APRIL-GAG interaction involved other regions than the APRIL N-terminus. Preferential interaction of APRIL with heparin followed by chondroitin sulfate E was confirmed by in silico analysis. Both computational and experimental approaches did not reveal the heparan sulfate binding to TACI. Together, computational results corroborated experiments contributing with atomistic details to the knowledge on this biologically relevant trimolecular system. Additionally, a high-throughput rigorous analysis of the free energy calculations data was performed to critically evaluate the applied computational methodologies.