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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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Interactions at hybrid/βTD and hybrid/EGF4 interfaces.A & B. Stereoviews of the post-equilibrated structures of U1 (A) and U2 (B) at the hybrid/βTD interface. C & D. Stereoviews of the post-equilibrated structures of U1 (C) and U2 (D) at the hybrid/EGF4 interface. Critical residues are shown as sticks. H-bonds are indicated by dashed lines. The hybrid, βTD, and EGF4 domains are colored in orange, pink, and tan, respectively.
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pcbi-1001086-g004: Interactions at hybrid/βTD and hybrid/EGF4 interfaces.A & B. Stereoviews of the post-equilibrated structures of U1 (A) and U2 (B) at the hybrid/βTD interface. C & D. Stereoviews of the post-equilibrated structures of U1 (C) and U2 (D) at the hybrid/EGF4 interface. Critical residues are shown as sticks. H-bonds are indicated by dashed lines. The hybrid, βTD, and EGF4 domains are colored in orange, pink, and tan, respectively.

Mentions: The hybrid/βTD interface was bound mainly by polar interactions, including a salt bridge between Asp393 and Arg633 (Figs. 4 A & B) as well as H-bonds whose number decreased from 8 to 0 as the simulations passed the major force peak (Figs. 3 and S1). In contrast, the hybrid/EGF4 interface was bound mainly by hydrophobic interactions, involving several nonpolar residues (Leu375, Ile380, Leu383, Met387, Met568, Leu573, and Leu574) (Figs. 4 C & D). In addition to the hydrophobic interactions, several H-bonds were observed at the hybrid/EGF4 interface for U2 (Fig. S2).


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)

Interactions at hybrid/βTD and hybrid/EGF4 interfaces.A & B. Stereoviews of the post-equilibrated structures of U1 (A) and U2 (B) at the hybrid/βTD interface. C & D. Stereoviews of the post-equilibrated structures of U1 (C) and U2 (D) at the hybrid/EGF4 interface. Critical residues are shown as sticks. H-bonds are indicated by dashed lines. The hybrid, βTD, and EGF4 domains are colored in orange, pink, and tan, respectively.
© Copyright Policy
Related In: Results  -  Collection

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

pcbi-1001086-g004: Interactions at hybrid/βTD and hybrid/EGF4 interfaces.A & B. Stereoviews of the post-equilibrated structures of U1 (A) and U2 (B) at the hybrid/βTD interface. C & D. Stereoviews of the post-equilibrated structures of U1 (C) and U2 (D) at the hybrid/EGF4 interface. Critical residues are shown as sticks. H-bonds are indicated by dashed lines. The hybrid, βTD, and EGF4 domains are colored in orange, pink, and tan, respectively.
Mentions: The hybrid/βTD interface was bound mainly by polar interactions, including a salt bridge between Asp393 and Arg633 (Figs. 4 A & B) as well as H-bonds whose number decreased from 8 to 0 as the simulations passed the major force peak (Figs. 3 and S1). In contrast, the hybrid/EGF4 interface was bound mainly by hydrophobic interactions, involving several nonpolar residues (Leu375, Ile380, Leu383, Met387, Met568, Leu573, and Leu574) (Figs. 4 C & D). In addition to the hydrophobic interactions, several H-bonds were observed at the hybrid/EGF4 interface for U2 (Fig. S2).

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