In computational studies of glycosaminoglycans (GAGs), a group of anionic, periodic linear polysaccharides, so far there has been very little discussion about the role of solvent models in the ...molecular dynamics simulations of these molecules. Predominantly, the TIP3P water model is commonly used as one of the most popular explicit water models in general. However, there are numerous alternative explicit and implicit water models that are neglected in the computational research of GAGs. Since solvent-mediated interactions are particularly important for GAG dynamic and structural properties, it would be of great interest for the GAG community to establish the solvent model that is suited the best in terms of the quality of theoretically obtained GAG parameters and, at the same time, would be reasonably demanding in terms of computational resources required. In this study, heparin (HP) was simulated using five implicit and six explicit solvent models with the aim to find out how different solvent models influence HP’s molecular descriptors in the molecular dynamics simulations. Here, we initiate the search for the most appropriate solvent representation for GAG systems and we hope to encourage other groups to contribute to this highly relevant subject.
Glycosaminoglycans (GAGs) made of repeating disaccharide units intricately engage with proteins, playing a crucial role in the spatial organization of the extracellular matrix (ECM) and the ...transduction of biological signals in cells to modulate a number of biochemical processes. Exploring protein–GAG interactions reveals several challenges for their analysis, namely, the highly charged and periodic nature of GAGs, their multipose binding, and the abundance of the interfacial water molecules in the protein–GAG complexes. Most of the studies on protein–GAG interactions are conducted using the TIP3P water model, and there are no data on the effect of various water models on the results obtained in molecular dynamics (MD) simulations of protein–GAG complexes. Hence, it is essential to perform a systematic analysis of different water models in MD simulations for these systems. In this work, we aim to evaluate the properties of the protein–GAG complexes in MD simulations using different explicit: TIP3P, SPC/E, TIP4P, TIP4PEw, OPC, and TIP5P and implicit: IGB = 1, 2, 5, 7, and 8 water models to find out which of them are best suited to study the dynamics of protein–GAG complexes. The FF14SB and GLYCAM06 force fields were used for the proteins and GAGs, respectively. The interactions of several GAG types, such as heparin, chondroitin sulfate, and hyaluronic acid with basic fibroblast growth factor, cathepsin K, and CD44 receptor, respectively, are investigated. The observed variations in different descriptors used to study the binding in these complexes emphasize the relevance of the choice of water models for the MD simulation of these complexes.
Docking glycosaminoglycans (GAGs) has been challenging because of the complex nature of these long periodic linear and negatively charged polysaccharides. Although standard docking tools like ...Autodock3 are successful when docking GAGs up to hexameric length, they experience challenges to properly dock longer GAGs. Similar limitations concern other docking approaches typically developed for docking ligands of limited size to proteins. At the same time, most of more advanced docking approaches are challenging for a user who is inexperienced with complex in silico methodologies. In this work, we evaluate the binding energies of complexes with different lengths of GAGs using all-atom molecular dynamics simulations. Based on this analysis, we propose a new docking protocol for long GAGs that consists of conventional docking of short GAGs and further elongation with the use of a coarse-grained representation of the GAG parts not being in direct contact with its protein receptor. This method automated by a simple script is straightforward to use within the Autodock3 framework but also useful in combination with other standard docking tools. We believe that this method with some minor case-specific modifications could also be used for docking other linear charged polymers.
Glycosaminoglycans represent a class of linear anionic periodic polysaccharides, which play a key role in a variety of biological processes in the extracellular matrix via interactions with their ...protein targets. Computationally, glycosaminoglycans are very challenging due to their high flexibility, periodicity and electrostatics-driven nature of the interactions with their protein counterparts. In this work, we carry out a detailed computational characterization of the interactions in protein-glycosaminoglycan complexes from the Protein Data Bank (PDB), which are split into two subsets accounting for their intrinsic nature: non-enzymatic-protein-glycosaminoglycan and enzyme-glycosaminoglycan complexes. We apply molecular dynamics to analyze the differences in these two subsets in terms of flexibility, retainment of the native interactions in the simulations, free energy components of binding and contributions of protein residue types to glycosaminoglycan binding. Furthermore, we systematically demonstrate that protein electrostatic potential calculations, previously found to be successful for glycosaminoglycan binding sites prediction for individual systems, are in general very useful for proposing protein surface regions as putative glycosaminoglycan binding sites, which can be further used for local docking calculations with these particular polysaccharides. Finally, the performance of six different docking programs (Autodock 3, Autodock Vina, MOE, eHiTS, FlexX and Glide), some of which proved to perform well for particular protein-glycosaminoglycan complexes in previous work, is evaluated on the complete protein-glycosaminoglycan data set from the PDB. This work contributes to widen our knowledge of protein-glycosaminoglycan molecular recognition and could be useful to steer a choice of the strategies to be applied in theoretical studies of these systems.
Heparin is an unbranched periodic polysaccharide composed of negatively charged monomers and involved in key biological processes, including anticoagulation, angiogenesis, and inflammation. Its ...structure and dynamics have been studied extensively using experimental as well as theoretical approaches. The conventional approach of computational chemistry applied to the analysis of biomolecules is all-atom molecular dynamics, which captures the interactions of individual atoms by solving Newton’s equation of motion. An alternative is molecular dynamics simulations using coarse-grained models of biomacromolecules, which offer a reduction of the representation and consequently enable us to extend the time and size scale of simulations by orders of magnitude. In this work, we extend the UNIfied COarse-gRaiNed (UNICORN) model of biological macromolecules developed in our laboratory to heparin. We carried out extensive tests to estimate the optimal weights of energy terms of the effective energy function as well as the optimal Debye–Hückel screening factor for electrostatic interactions. We applied the model to study unbound heparin molecules of polymerization degree ranging from 6 to 68 residues. We compare the obtained coarse-grained heparin conformations with models obtained from X-ray diffraction studies of heparin. The SUGRES-1P force field was able to accurately predict the general shape and global characteristics of heparin molecules.
Glycosaminoglycans (GAGs) are a class of periodic anionic linear polysaccharides involved in a number of biologically relevant processes in the extracellular matrix via interactions with various ...types of molecules including proteins, peptides and small organic molecules. The metachromatic dye methylene blue (MB) is a GAG binding agent. This molecule possesses a tricyclic, monocationic phenothiazine ring system, while the terminal methyl groups attached to the nitrogen atoms bear the most positive charges of the cation and, therefore, represent potential binding sites for negatively charged GAGs. In this study, we rigorously explored molecular mechanisms underlying these interactions for several GAG types: heparin, heparan and chondroitin sulfates. We found that GAG-MB interactions are predominantly electrostatically driven, with the particularly important role of sulfate groups. MB oligomeric stack formation was favored in the presence of GAGs. Furthermore, the impact of MB binding on the conformation of GAGs was also evaluated. The novel results allow for better quantitative analytics of GAG composition in the studied biochemical systems using MB dye as a GAG-specific marker. Our data add to the knowledge on small molecule-GAG interactions and could be potentially useful for novel developments in drug design and putative disease therapies in which GAGs are involved.
Cysteine cathepsins constitute the largest cathepsin family, with 11 proteases in human that are present primarily within acidic endosomal and lysosomal compartments. They are involved in the ...turnover of intracellular and extracellular proteins. They are synthesized as inactive procathepsins that are converted to mature active forms. Cathepsins play important roles in physiological and pathological processes and, therefore, receive increasing attention as potential therapeutic targets. Their maturation and activity can be regulated by glycosaminoglycans (GAGs), long linear negatively charged polysaccharides composed of recurring dimeric units. In this review, we summarize recent computational progress in the field of (pro)cathepsin-GAG complexes analyses.
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•Molecular modeling is crucial for better understanding GAG-mediated procathepsin maturation mechanisms at the atomic level.•In silico methods allow to study effect of length, charge and sulfation pattern on stability of cathepsin-GAG complexes.•Application of computational methods is essential in elucidating GAGs role in cathepsins enzymatic activity mediation.
Modeling glycosaminoglycan–protein complexes Kogut, Małgorzata M.; Marcisz, Mateusz; Samsonov, Sergey A.
Current opinion in structural biology,
April 2022, 2022-04-00, 20220401, Letnik:
73
Journal Article
Recenzirano
Glycosaminoglycans are long linear and complex polysaccharides that are fundamental components of the mammalian extracellular matrix. Therefore, it is crucial to appropriately characterize molecular ...structure, dynamics, and interactions of protein-glycosaminoglycans complexes for improving understanding of molecular mechanisms underlying GAG biological function. Nevertheless, this proved challenging experimentally, and theoretical techniques are beneficial to construct new hypotheses and aid the interpretation of experimental data. The scope of this mini-review is to summarize four specific aspects of the current theoretical approaches for investigating noncovalent protein-glycosaminoglycan complexes such as molecular docking, free binding energy calculations, modeling ion impact, and addressing the phenomena of multipose binding of glycosaminoglycans to proteins.
•Dedicated molecular docking approaches are required for protein-glycosaminoglycan (GAG) systems.•Despite its limitations, molecular mechanics/Poisson-Boltzmann surface area remains the most useful free energy analysis tool.•The role of ions in protein-GAG interfaces should not be disregarded.•Multipose binding is an essential feature in protein-GAG modeling.
The interaction of regulatory proteins with extracellular matrix or cell surface-anchored glycosaminoglycans (GAGs) plays important roles in molecular recognition, wound healing, growth, inflammation ...and many other processes. In spite of their high biological relevance, protein-GAG complexes are significantly underrepresented in structural databases because standard tools for structure determination experience difficulties in studying these complexes. Co-crystallization with subsequent X-ray analysis is hampered by the high flexibility of GAGs. NMR spectroscopy experiences difficulties related to the periodic nature of the GAGs and the sparse proton network between protein and GAG with distances that typically exceed the detection limit of nuclear Overhauser enhancement spectroscopy. In contrast, computer modeling tools have advanced over the last years delivering specific protein-GAG docking approaches successfully complemented with molecular dynamics (MD)-based analysis. Especially the combination of NMR spectroscopy in solution providing sparse structural constraints with molecular docking and MD simulations represents a useful synergy of forces to describe the structure of protein-GAG complexes. Here we review recent methodological progress in this field and bring up examples where the combination of new NMR methods along with cutting-edge modeling has yielded detailed structural information on complexes of highly relevant cytokines with GAGs.
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