Evaluation of replica exchange with repulsive scaling approach for docking glycosaminoglycans

Abstract

Glycosaminoglycans (GAGs), long linear periodic anionic polysaccharides, are key molecules in the extracellular matrix (ECM). Therefore, deciphering their role in the biologically relevant context is important for fundamental understanding of the processes ongoing in ECM and for establishing new strategies in the regenerative medicine. Although GAGs represent a number of computational challenges, molecular docking is a powerful tool for analysis of their interactions. Despite the recent development of GAG‐specific docking approaches, there is plenty of room for improvement. Here, replica exchange molecular dynamics with repulsive scaling (REMD‐RS) recently proved to be a successful approach for protein–protein complexes, was applied to dock GAGs. In this method, effective pairwise radii are increased in different Hamiltonian replicas. REMD‐RS is shown to be an attractive alternative to classical docking approaches for GAGs. This work contributes to setting up of GAG‐specific computational protocols and provides new insights into the nature of these biological systems.

The potential role of glycosaminoglycans in serum amyloid A fibril formation by in silico approaches

“…Furthermore, we aimed to verify the structures obtained by the molecular docking and conventional MD by the RS-REMD approach, which previously was shown to perform very well for protein-GAG complexes [32] . This method allows to correctly predict a binding site and produces an ensemble of GAG-protein complex structures using an implicit solvent model, while its performance is independent of the GAG length.…”

“…Interestingly, for the SAA dimer/HP dp6 complex the ligand docked to both first and second N-terminal fragments, but did not dock in the middle of the helices as it did when we performed docking by Autodock. This is related to the fact that RS-REMD approach experience difficulties when a binding site is not exposed on the protein surface but rather has a cavity topology [32] . 100 best SAA dimer/HP dp6 complex structures in Fig.…”

“…For the Repulsive Scaling Replica Exchange Molecular Dynamics (RS-REMD) [44] simulations the protocol as presented in our previous work on protein-GAG complexes was applied [32] . The HP dp6 and dp24 and the SAA dimer and monomer were used as ligands and receptors, respectively.…”

“…The refinement of the structures obtained in the RS-REMD step was performed based on electrostatic energy values obtained from the MM-GBSA calculations as described in our previous work [32] . First, the binding free energy was calculated in AMBER16 [33] program.…”

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

“…The RS-REMD (replica exchange molecular dynamics with repulsive scaling) method [ 22 , 23 ] is not restricted by any of the above-mentioned limits. Moreover, it has been proven that this method is appropriate to dock GAGs [ 24 ]. In RS-REMD, effective pairwise radii are increased in different Hamiltonian replicas.…”