Link module domains play an essential role in extracellular matrix assembly
andremodeling by binding to the flexible glycosaminoglycan hyaluronan. A high-resolution NMR-structure of the Link module from the protein product of tumor necrosis factor-stimulated gene-6(Link_TSG6) has been determined, but a fuller appreciation of protein dynamics may benecessary to underst
and its hyaluronan-binding. Therefore, we have performed a 0.25
s MDsimulation, starting from the lowest-energy NMR-derived solution structure of Link_TSG6, withexplicit water
and ions, using the CHARMM22 protein force field. The simulation was as gooda fit to the NMR data as the ensemble from simulated annealing, except in the
5-
6 loop.Furthermore, analysis revealed that secondary structure elements extended further thanpreviously reported
and underwent fast picosecond time scale dynamics, whereas nanoseconddynamics was found in certain loops. In particular, surface side chains proposed to interactwith glycosaminoglycans were predicted to be highly mobile
and be directed away from theprotein surface. Furthermore, the hyaluronan-binding
4-
5 loop remained in a closedconformation, favoring an allosteric interaction mechanism. This enhanced view of the Linkmodule provides general insight into protein dynamics
and may be helpful for underst
andingthe dynamic molecular basis of tissue assembly, remodeling,
and disease processes.