HMGB1-carbenoxolone interactions: Dynamics insights from combined nuclear magnetic resonance and molecular dynamics

Luca Mollica, Giulia Morra, Giorgio Colombo, Giovanna Musco

Research output: Contribution to journalArticlepeer-review

Abstract

The interplay of protein dynamics and molecular recognition is of fundamental importance in biological processes. Atomic-resolution insights into these phenomena may provide new opportunities for drug discovery. Herein, we have combined NMR relaxation experiments and residual dipolar coupling (RDC) measurements with molecular dynamics (MD) simulations to study the effects of the anti-inflammatory drug carbenoxolone (CBNX) on the conformational properties and on the internal dynamics of a subdomain (box A) of high-mobility group B protein (HMGB1). 15N relaxation data show that CBNX binding enhances the fast pico- to nanosecond motions of a loop and partially removes the internal motional anisotropy of the first two helices of box A. Dipolar wave analysis of amide RDC data shows that ligand binding induces helical distortions. In parallel, increased mobility of the loop upon ligand binding is highlighted by the essential dynamics analysis (EDA) of MD simulations. Moreover, simulations detect two possible orientations for CBNX, which induces two possible conformations of helix H3, one being similar to the free form and the second one causing a partial helical distortion. Finally, we introduce a new approach for the analysis of the internal coordination of protein residues that is consistent with experimental data and allows us to pinpoint which substructures of box A are dynamically affected by CBNX. The observations reported here may be useful for understanding the role of protein dynamics in binding at atomic resolution. Drugged and bound: A combination of NMR relaxation and residual dipolar coupling measurements with molecular dynamics simulations have been used to investigate the influence of the anti-inflammatory drug carbenoxolone (CBNX) on the conformational ensemble of box A of high-mobility group B protein (HMGB1; see picture).

Original languageEnglish
Pages (from-to)1171-1180
Number of pages10
JournalChemistry - An Asian Journal
Volume6
Issue number5
DOIs
Publication statusPublished - May 2 2011

Keywords

  • carbenoxolone
  • drug design
  • helical structures
  • molecular dynamics
  • proteins

ASJC Scopus subject areas

  • Chemistry(all)
  • Medicine(all)

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