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Molecular dynamics simulations of forced unbending of integrin α(v)β₃.

Chen W, Lou J, Hsin J, Schulten K, Harvey SC, Zhu C - PLoS Comput. Biol. (2011)

Bottom Line: By comparison, a fully-extended conformation was stable.A newly-formed coordination between the α(v) Asp457 and the α-genu metal ion might contribute to the stability of the fully-extended conformation.These results reveal the dynamic processes and pathways of integrin conformational changes with atomic details and provide new insights into the structural mechanisms of integrin activation.

View Article: PubMed Central - PubMed

Affiliation: Woodruff School of Mechanical Engineering, Georgia Institute of Technology, Atlanta, Georgia, United States of America.

ABSTRACT
Integrins may undergo large conformational changes during activation, but the dynamic processes and pathways remain poorly understood. We used molecular dynamics to simulate forced unbending of a complete integrin α(v)β₃ ectodomain in both unliganded and liganded forms. Pulling the head of the integrin readily induced changes in the integrin from a bent to an extended conformation. Pulling at a cyclic RGD ligand bound to the integrin head also extended the integrin, suggesting that force can activate integrins. Interactions at the interfaces between the hybrid and β tail domains and between the hybrid and epidermal growth factor 4 domains formed the major energy barrier along the unbending pathway, which could be overcome spontaneously in ~1 µs to yield a partially-extended conformation that tended to rebend. By comparison, a fully-extended conformation was stable. A newly-formed coordination between the α(v) Asp457 and the α-genu metal ion might contribute to the stability of the fully-extended conformation. These results reveal the dynamic processes and pathways of integrin conformational changes with atomic details and provide new insights into the structural mechanisms of integrin activation.

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Forced unbending of liganded integrin αVβ3.A. Snapshots of a liganded integrin αVβ3 in the bent and fully-extended conformations at the indicated times and extensions in the L1 SMD 1. The βTD was constrained as shown by a circle. The RGD ligand (green spheres, same color coding and representations in all figures and videos) where force was loaded was zoomed-in to show the ligand binding site with a different orientation for better display, where the RGD ligand is shown as sticks and three Mg2+ ions as red spheres. LIMBS, ligand-associated metal binding site; ADMIDAS, adjacent to MIDAS. B. Time courses of distances between the ligand Arg and the αV Asp218 (red and blue) or between the ligand Asp and the αV MIDAS Mg2+ (magenta and cyan) in the L1 SMD 1 (red and magenta) and L2 SMD (blue and cyan). Some of the curves were obscured due to overlapping. C. Force-extension curves for the indicated SMD simulations. The U1 SMD 1 curve was replotted for comparison.
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pcbi-1001086-g009: Forced unbending of liganded integrin αVβ3.A. Snapshots of a liganded integrin αVβ3 in the bent and fully-extended conformations at the indicated times and extensions in the L1 SMD 1. The βTD was constrained as shown by a circle. The RGD ligand (green spheres, same color coding and representations in all figures and videos) where force was loaded was zoomed-in to show the ligand binding site with a different orientation for better display, where the RGD ligand is shown as sticks and three Mg2+ ions as red spheres. LIMBS, ligand-associated metal binding site; ADMIDAS, adjacent to MIDAS. B. Time courses of distances between the ligand Arg and the αV Asp218 (red and blue) or between the ligand Asp and the αV MIDAS Mg2+ (magenta and cyan) in the L1 SMD 1 (red and magenta) and L2 SMD (blue and cyan). Some of the curves were obscured due to overlapping. C. Force-extension curves for the indicated SMD simulations. The U1 SMD 1 curve was replotted for comparison.

Mentions: We next performed constant-velocity SMD simulations to unbend the liganded integrin αVβ3 (L1 or L2) by pulling its bound cyclic RGD ligand away from the constrained βTD domain (Fig. 9A). In the L1 SMD 1 and L2 SMD, the integrin readily unbent with the ligand remained bound within 10 ns (Fig. 9A and Video S5 & S6). Compared to the unliganded integrin, the liganded integrin also reached a fully extended conformation with a closed headpiece, but the legs showed a greater degree of relative rotation.


Molecular dynamics simulations of forced unbending of integrin α(v)β₃.

Chen W, Lou J, Hsin J, Schulten K, Harvey SC, Zhu C - PLoS Comput. Biol. (2011)

Forced unbending of liganded integrin αVβ3.A. Snapshots of a liganded integrin αVβ3 in the bent and fully-extended conformations at the indicated times and extensions in the L1 SMD 1. The βTD was constrained as shown by a circle. The RGD ligand (green spheres, same color coding and representations in all figures and videos) where force was loaded was zoomed-in to show the ligand binding site with a different orientation for better display, where the RGD ligand is shown as sticks and three Mg2+ ions as red spheres. LIMBS, ligand-associated metal binding site; ADMIDAS, adjacent to MIDAS. B. Time courses of distances between the ligand Arg and the αV Asp218 (red and blue) or between the ligand Asp and the αV MIDAS Mg2+ (magenta and cyan) in the L1 SMD 1 (red and magenta) and L2 SMD (blue and cyan). Some of the curves were obscured due to overlapping. C. Force-extension curves for the indicated SMD simulations. The U1 SMD 1 curve was replotted for comparison.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3040657&req=5

pcbi-1001086-g009: Forced unbending of liganded integrin αVβ3.A. Snapshots of a liganded integrin αVβ3 in the bent and fully-extended conformations at the indicated times and extensions in the L1 SMD 1. The βTD was constrained as shown by a circle. The RGD ligand (green spheres, same color coding and representations in all figures and videos) where force was loaded was zoomed-in to show the ligand binding site with a different orientation for better display, where the RGD ligand is shown as sticks and three Mg2+ ions as red spheres. LIMBS, ligand-associated metal binding site; ADMIDAS, adjacent to MIDAS. B. Time courses of distances between the ligand Arg and the αV Asp218 (red and blue) or between the ligand Asp and the αV MIDAS Mg2+ (magenta and cyan) in the L1 SMD 1 (red and magenta) and L2 SMD (blue and cyan). Some of the curves were obscured due to overlapping. C. Force-extension curves for the indicated SMD simulations. The U1 SMD 1 curve was replotted for comparison.
Mentions: We next performed constant-velocity SMD simulations to unbend the liganded integrin αVβ3 (L1 or L2) by pulling its bound cyclic RGD ligand away from the constrained βTD domain (Fig. 9A). In the L1 SMD 1 and L2 SMD, the integrin readily unbent with the ligand remained bound within 10 ns (Fig. 9A and Video S5 & S6). Compared to the unliganded integrin, the liganded integrin also reached a fully extended conformation with a closed headpiece, but the legs showed a greater degree of relative rotation.

Bottom Line: By comparison, a fully-extended conformation was stable.A newly-formed coordination between the α(v) Asp457 and the α-genu metal ion might contribute to the stability of the fully-extended conformation.These results reveal the dynamic processes and pathways of integrin conformational changes with atomic details and provide new insights into the structural mechanisms of integrin activation.

View Article: PubMed Central - PubMed

Affiliation: Woodruff School of Mechanical Engineering, Georgia Institute of Technology, Atlanta, Georgia, United States of America.

ABSTRACT
Integrins may undergo large conformational changes during activation, but the dynamic processes and pathways remain poorly understood. We used molecular dynamics to simulate forced unbending of a complete integrin α(v)β₃ ectodomain in both unliganded and liganded forms. Pulling the head of the integrin readily induced changes in the integrin from a bent to an extended conformation. Pulling at a cyclic RGD ligand bound to the integrin head also extended the integrin, suggesting that force can activate integrins. Interactions at the interfaces between the hybrid and β tail domains and between the hybrid and epidermal growth factor 4 domains formed the major energy barrier along the unbending pathway, which could be overcome spontaneously in ~1 µs to yield a partially-extended conformation that tended to rebend. By comparison, a fully-extended conformation was stable. A newly-formed coordination between the α(v) Asp457 and the α-genu metal ion might contribute to the stability of the fully-extended conformation. These results reveal the dynamic processes and pathways of integrin conformational changes with atomic details and provide new insights into the structural mechanisms of integrin activation.

Show MeSH