Ligand binding: Molecular mechanics calculation of the streptavidin-biotin rupture force

Science

Volumn 271, Issue 5251, 1996, Pages 997-999

  Grubmüller, Helmut ^a   Heymann, Berthold ^a   Tavan, Paul ^a  

^a UNIVERSITY OF MUNICH   (Germany)

Author keywords

[No Author keywords available]

Indexed keywords

BIOTIN; STREPTAVIDIN;

ARTICLE; COMPUTER SIMULATION; FORCE; HYDROGEN BOND; LIGAND BINDING; MOLECULAR DYNAMICS; MOLECULAR STABILITY; PRIORITY JOURNAL; PROTEIN BINDING; PROTEIN PROTEIN INTERACTION;

EID: 0030059225     PISSN: 00368075     EISSN: None     Source Type: Journal    
DOI: 10.1126/science.271.5251.997     Document Type: Article

References (31)

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10. For algorithmic advances, see C. Niedermeier and P. Tavan, J Chem Phys. 101, 734 (1994); M. Eichinger, H. Grubmuller, H. Heller, P. Tavan, in preparation; and H. Grubmüller, Phys. Rev. E 52, 2893 (1995) and references therein. For parallel computing, see (17) and H. Heller, H. Grubmuller, K. Schulten, Mol Simul. 5, 133 (1990).
11. For algorithmic advances, see C. Niedermeier and P. Tavan, J Chem Phys. 101, 734 (1994); M. Eichinger, H. Grubmuller, H. Heller, P. Tavan, in preparation; and H. Grubmüller, Phys. Rev. E 52, 2893 (1995) and references therein. For parallel computing, see (17) and H. Heller, H. Grubmuller, K. Schulten, Mol Simul. 5, 133 (1990).
12. For algorithmic advances, see C. Niedermeier and P. Tavan, J Chem Phys. 101, 734 (1994); M. Eichinger, H. Grubmuller, H. Heller, P. Tavan, in preparation; and H. Grubmüller, Phys. Rev. E 52, 2893 (1995) and references therein. For parallel computing, see (17) and H. Heller, H. Grubmuller, K. Schulten, Mol Simul. 5, 133 (1990).
13. For algorithmic advances, see C. Niedermeier and P. Tavan, J Chem Phys. 101, 734 (1994); M. Eichinger, H. Grubmuller, H. Heller, P. Tavan, in preparation; and H. Grubmüller, Phys. Rev. E 52, 2893 (1995) and references therein. For parallel computing, see (17) and H. Heller, H. Grubmuller, K. Schulten, Mol Simul. 5, 133 (1990).
14. Alternativeiy, one may compute the free energy profile along the unbinding reaction path from the MD simulation and derive the rupture force from that profile However, because free energies pertain to systems in equilibrium, this suggested equilibrium approach rests on the questionable assumption that the rupture is a quasi-stationary process Furthermore, it requires computations of free energies that notoriously exhibit slow convergence. Thus, in this case our nonequilibnum approach appears to be more appropriate and is computationally less expensive.
15. 120 of the neighboring streptavidin monomer and the biotin in the binding pocket is considerably weaker than that for avidin (3).
16. -1) After minimization, the system was equilibrated for 500 ps because it exhibited relaxations for more than 300 ps After relaxation, the protein backbone atoms showed a root mean square deviation from the x-ray structure of 2.6 Å. Closer inspection revealed that a large fraction of the observed deviation arose from two loops (residues 65 to 70 and 112 to 122) at the tetramer interface, both of which are flexible in our monomer model but fixed by intermofecular interactions in the tetramer The geometry of the binding pocket in our model does not deviate significantly from that of the x-ray structure (root mean square deviation, 1.5 Å). Structures randomly extracted from a subsequent MD run of 20 ps in duration were used for the simulations described in the text.
17. o2 of roughly 0.4 Å, a value commonly observed for unperturbed atomic fluctuations in proteins. Therefore, the thermal motion of the pulled atom is essentially unaffected by the spring potential.
18. We note that thermal fluctuations enlail a logarithmic dependency of the rupture force on the pulling velocity (2); however, for the large velocities studied in our simulations, a linear dependency due to friction dominates This friction heats the binding region by, at most. 3 K in the case of our slowest simulation. That heat is then effectively transferred to the heat bath; see (10).
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20. 1 within which the cantilever was moved by 15 Å Considering the structural heterogeneity mentioned above, one cannot expect the finest details of the simulation or of the force profile to be reproducible Therefore, we restrict our discussion to those typical features, which appeared in several of our simulations We emphasize, however, that many more interactions contribute to the binding forces than those discussed here and that the rupture process is more complex than our simplifying pictures may suggest.
21. All hydrogen bonds found after equilibration are also found In the x-ray structure [P. C. Weber et al., J. Am Chem. Soc. 114, 3197 (1992)].
22. For subtle reasons, simple integration of our force profile does not yield correct equilibrium binding free energies. The question of whether and how these can be obtained from our simulations is, therefore, left for future discussion.
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29. The figure was prepared with the use of MOLSCRIPT [P J. Kraulis, J. Appt. Crystallogr. 24, 946 (1991)1.
30. The computed force profiles exhibit fast fluctuations caused by (artificial) resonance of our spring. Accordingly, by simply taking the maximum force from these unprocessed profiles, one overestimates the rupture force Therefore, before computing rupture forces, we removed the fast fluctuations by smoothing the force profiles with a Gaussian distribution of 4 ps wioh; that width has been estimated from the decay of the position autocorrelation function of atom O2 (compare Rig. 1B). This approach introduces some arbitrariness into the force computation, because the maximum force depends on the smoothing width. To quantify that uncertainty, we determined error bars by considering force profiles smoothed on the scale of 2 ps (providing an upper bound) and 8 ps (lower bound), respectively
31. We thank H. Gaub for stimulating this work, V Moy for explaining details of the AFM experiment, and M Eichinger and H. Heller for discussions and help with the program EGO. Supported by the Deutsche Forschungsgemeinschaft, grant SFB 143/C1. For more information see .