Using molecular dynamics simulations to provide new insights into protein structure on the nanosecond timescale: Comparison with experimental data and biological inferences for the hyaluronan-binding link module of TSG-6

Andrew Almond*, Charles D. Blundell, Victoria A. Higman, Alexander D. MacKerell, Anthony J. Day

*Corresponding author for this work

Research output: Contribution to journalArticle (Academic Journal)peer-review

7 Citations (Scopus)

Abstract

Link module domains play an essential role in extracellular matrix assembly and remodeling 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 be necessary to understand its hyaluronan-binding. Therefore, we have performed a 0.25 mu s MD simulation, starting from the lowest-energy NMR-derived solution structure of Link_TSG6, with explicit water and ions, using the CHARMM22 protein force field. The simulation was as good a fit to the NMR data as the ensemble from simulated annealing, except in the beta 5-beta 6 loop. Furthermore, analysis revealed that secondary structure elements extended further than previously reported and underwent fast picosecond time scale dynamics, whereas nanosecond dynamics was found in certain loops. In particular, surface side chains proposed to interact with glycosaminoglycans were predicted to be highly mobile and be directed away from the protein surface. Furthermore, the hyaluronan-binding beta 4-beta 5 loop remained in a closed conformation, favoring an allosteric interaction mechanism. This enhanced view of the Link module provides general insight into protein dynamics and may be helpful for understanding the dynamic molecular basis of tissue assembly, remodeling, and disease processes.

Original languageEnglish
Pages (from-to)1-16
Number of pages16
JournalJournal of Chemical Theory and Computation
Volume3
Issue number1
DOIs
Publication statusPublished - 2007

Keywords

  • BACKBONE DYNAMICS
  • NMR RELAXATION
  • LIQUID WATER
  • SIDE-CHAINS
  • FORCE-FIELDS
  • AQUEOUS-SOLUTION
  • CONFORMATION
  • RESIDUAL DIPOLAR COUPLINGS
  • HYDROGEN-EXCHANGE
  • FACTOR-STIMULATED GENE-6

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