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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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Constant-force SMD simulations.A. Head-tail distances vs. time of constant-force SMD simulations with the indicated forces. One simulation for U2 is indicated in parentheses and the others are for U1. Downward arrows indicate the moments when unbending started. A rightward arrow indicates an intermediate state. B. Natural log of waiting time t (in ns) for unbending vs. force data (symbols) and the Bell model fit (line) to the U1 data.
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pcbi-1001086-g006: Constant-force SMD simulations.A. Head-tail distances vs. time of constant-force SMD simulations with the indicated forces. One simulation for U2 is indicated in parentheses and the others are for U1. Downward arrows indicate the moments when unbending started. A rightward arrow indicates an intermediate state. B. Natural log of waiting time t (in ns) for unbending vs. force data (symbols) and the Bell model fit (line) to the U1 data.

Mentions: To complement and compare with the constant-velocity SMD simulations, we performed a series of constant-force SMD simulations for U1 and U2, where constant forces were loaded to the βA domain along the same direction with the βTD constrained as before. Instead of repeating the simulations at the same force, we used five forces from 97–195 pN for U1 and a 195 pN force for U2. Upon application of force, the head-tail distance was held at 4–5 nm initially, indicating the stability of the bent conformation, then increased suddenly, indicating a rapid conformational transition, and finally leveled off, indicating full extension (Fig. 6A). The rapid transition occurred after disrupting the interactions that gave rise to the major force peaks in the constant-velocity SMD simulations, confirming that these interactions provided the major barrier to unbending. In most cases, the interactions at both the hybrid/βTD and the hybrid/EGF4 interfaces were disrupted simultaneously. In the 146 and 97 pN constant-force simulations, however, the interactions at the hybrid/βTD interface were disrupted first, resulting in an initial slow-increase phase in the head-tail distance until the interactions at the hybrid/EGF4 interface were also broken. In the 122 pN constant-force simulation, the unbending process was slowed down in the middle of the conformational transition because of the interactions at the knees between the EGF1 and EGF2 domains and between the calf-1 and calf-2 domains. Interestingly, during the simulation with the lowest force of 97 pN, an intermediate state was observed, manifesting as a short plateau with a head-tail distance of ∼12 nm (Fig. 6A, rightward arrow). In the intermediate state the interactions at both the hybrid/βTD and hybrid/EGF4 interfaces were disrupted, but the interactions near the knees were still held.


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)

Constant-force SMD simulations.A. Head-tail distances vs. time of constant-force SMD simulations with the indicated forces. One simulation for U2 is indicated in parentheses and the others are for U1. Downward arrows indicate the moments when unbending started. A rightward arrow indicates an intermediate state. B. Natural log of waiting time t (in ns) for unbending vs. force data (symbols) and the Bell model fit (line) to the U1 data.
© Copyright Policy
Related In: Results  -  Collection

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

pcbi-1001086-g006: Constant-force SMD simulations.A. Head-tail distances vs. time of constant-force SMD simulations with the indicated forces. One simulation for U2 is indicated in parentheses and the others are for U1. Downward arrows indicate the moments when unbending started. A rightward arrow indicates an intermediate state. B. Natural log of waiting time t (in ns) for unbending vs. force data (symbols) and the Bell model fit (line) to the U1 data.
Mentions: To complement and compare with the constant-velocity SMD simulations, we performed a series of constant-force SMD simulations for U1 and U2, where constant forces were loaded to the βA domain along the same direction with the βTD constrained as before. Instead of repeating the simulations at the same force, we used five forces from 97–195 pN for U1 and a 195 pN force for U2. Upon application of force, the head-tail distance was held at 4–5 nm initially, indicating the stability of the bent conformation, then increased suddenly, indicating a rapid conformational transition, and finally leveled off, indicating full extension (Fig. 6A). The rapid transition occurred after disrupting the interactions that gave rise to the major force peaks in the constant-velocity SMD simulations, confirming that these interactions provided the major barrier to unbending. In most cases, the interactions at both the hybrid/βTD and the hybrid/EGF4 interfaces were disrupted simultaneously. In the 146 and 97 pN constant-force simulations, however, the interactions at the hybrid/βTD interface were disrupted first, resulting in an initial slow-increase phase in the head-tail distance until the interactions at the hybrid/EGF4 interface were also broken. In the 122 pN constant-force simulation, the unbending process was slowed down in the middle of the conformational transition because of the interactions at the knees between the EGF1 and EGF2 domains and between the calf-1 and calf-2 domains. Interestingly, during the simulation with the lowest force of 97 pN, an intermediate state was observed, manifesting as a short plateau with a head-tail distance of ∼12 nm (Fig. 6A, rightward arrow). In the intermediate state the interactions at both the hybrid/βTD and hybrid/EGF4 interfaces were disrupted, but the interactions near the knees were still held.

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