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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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Changes in headpiece-tailpiece interactions near the major force peaks.Buried SASAs (upper row, left ordinate) and numbers of H-bonds (lower row, left ordinate) of the hybrid (blue), βA (cyan), EGF4 (red), and βTD (magenta) domains as well as pulling force (gray, both rows, right ordinate) were plotted vs. extensions for the U1 SMD 1 (left column) and U2 SMD (right column). Some of the curves were obscured due to overlapping.
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pcbi-1001086-g003: Changes in headpiece-tailpiece interactions near the major force peaks.Buried SASAs (upper row, left ordinate) and numbers of H-bonds (lower row, left ordinate) of the hybrid (blue), βA (cyan), EGF4 (red), and βTD (magenta) domains as well as pulling force (gray, both rows, right ordinate) were plotted vs. extensions for the U1 SMD 1 (left column) and U2 SMD (right column). Some of the curves were obscured due to overlapping.

Mentions: To elucidate the cause of the major force peak(s), we analyzed the buried SASAs and hydrogen bonds (H-bonds) between the headpiece and tailpiece for different integrin domains (Fig. 3). The decrease in the buried SASAs of different domains during integrin unbending revealed the disruption of interdomain interactions as the originally buried surfaces were exposed. The drops of the buried SASAs of the hybrid, βTD, and EGF4 domains were found to coincide with the major force peak (Figs. 3 and S1), identifying the interactions at the hybrid/βTD and hybrid/EGF4 interfaces as the major barrier to unbending. Interactions between the βA domain and βTD also contributed to the major force peak for U2, but these interactions were broken spontaneously during the equilibration of U1 and thus not seen in the U1 SMD simulations (cyan curves in Figs. 3 and S1). In the U1 SMD 1 & 2, interactions at the two interfaces were broken at the same time. However, in the U1 SMD 3 and the U2 SMD, interactions at the hybrid/βTD interface were broken before those at the hybrid/EGF4 interface, giving rise to a small bump after the major force peak in the U1 SMD 3 and splitting the major force peak into two in the U2 SMD (gray curves in Figs. 3 and S1).


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)

Changes in headpiece-tailpiece interactions near the major force peaks.Buried SASAs (upper row, left ordinate) and numbers of H-bonds (lower row, left ordinate) of the hybrid (blue), βA (cyan), EGF4 (red), and βTD (magenta) domains as well as pulling force (gray, both rows, right ordinate) were plotted vs. extensions for the U1 SMD 1 (left column) and U2 SMD (right column). Some of the curves were obscured due to overlapping.
© Copyright Policy
Related In: Results  -  Collection

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

pcbi-1001086-g003: Changes in headpiece-tailpiece interactions near the major force peaks.Buried SASAs (upper row, left ordinate) and numbers of H-bonds (lower row, left ordinate) of the hybrid (blue), βA (cyan), EGF4 (red), and βTD (magenta) domains as well as pulling force (gray, both rows, right ordinate) were plotted vs. extensions for the U1 SMD 1 (left column) and U2 SMD (right column). Some of the curves were obscured due to overlapping.
Mentions: To elucidate the cause of the major force peak(s), we analyzed the buried SASAs and hydrogen bonds (H-bonds) between the headpiece and tailpiece for different integrin domains (Fig. 3). The decrease in the buried SASAs of different domains during integrin unbending revealed the disruption of interdomain interactions as the originally buried surfaces were exposed. The drops of the buried SASAs of the hybrid, βTD, and EGF4 domains were found to coincide with the major force peak (Figs. 3 and S1), identifying the interactions at the hybrid/βTD and hybrid/EGF4 interfaces as the major barrier to unbending. Interactions between the βA domain and βTD also contributed to the major force peak for U2, but these interactions were broken spontaneously during the equilibration of U1 and thus not seen in the U1 SMD simulations (cyan curves in Figs. 3 and S1). In the U1 SMD 1 & 2, interactions at the two interfaces were broken at the same time. However, in the U1 SMD 3 and the U2 SMD, interactions at the hybrid/βTD interface were broken before those at the hybrid/EGF4 interface, giving rise to a small bump after the major force peak in the U1 SMD 3 and splitting the major force peak into two in the U2 SMD (gray curves in Figs. 3 and S1).

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