Heparin is a key player in cell signaling via its physical interactions with protein targets in the extracellular matrix. However, basic molecular level understanding of these highly biologically relevant intermolecular interactions is still incomplete. In this study, for the first time, microsecond-scale MD simulations are reported for a complex between fibroblast growth factor 1 and heparin. We rigorously analyze this molecular system in terms of the conformational space, structural, energetic, and dynamic characteristics. We reveal that the conformational selection mechanism of binding denotes a recognition specificity determinant. We conclude that the length of the simulation could be crucial for evaluation of some of the analyzed parameters. Our data provide novel significant insights into the interactions in the fibroblast growth factor 1 complex with heparin, in particular, and into the physical-chemical nature of protein-glycosaminoglycan systems in general, which have potential applicability for biomaterials development in the area of regenerative medicine.
K E Y W O R D Sfibroblast growth factor 1, heparin conformational analysis, molecular dynamics, proteinglycosaminoglycan interactions, ring puckering
Heparin belongs to glycosaminoglycans (GAGs), a class of periodic linear anionic polysaccharides, which are functionally important components of the extracellular matrix owing to their interactions with various protein targets. Heparin is known to be involved in many cell signaling processes, while the experimental data available for heparin are significantly more abundant than for other GAGs. At the same time, the length and conformational flexibility of the heparin represent major challenges for its theoretical analysis. Coarse‐grained (CG) approaches, which enable us to extend the size‐ and time‐scale by orders of magnitude owing to reduction of system representation, appear, therefore, to be useful in simulating these systems. In this work, by using umbrella‐sampling molecular dynamics simulations, we derived and parameterized the CG backbone‐local potentials of heparin chains and the orientational potentials for the interactions of heparin with amino acid side chains to be further included in the physics‐based Unified Coarse‐Grained Model of biological macromolecules. With these potentials, simulations of extracellular matrix processes where both heparin and multiple proteins participate will be possible.
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