DOI: 10.1110/ps.041280705. Change of the unbinding mechanism upon a mutation: A molecular dynamics study of an antibody

Change of the unbinding mechanism upon a mutation: A molecular dynamics study of an antibody–hapten complex

10.1110/ps.041280705

Crossref journal-article

Wiley

Protein Science (311)

Abstract

AbstractWe study forced unbinding of fluorescein from the wild type (WT) and a mutant [H(H58)A] of the single‐chain variable‐fragment (scFv) anti‐fluorescein antibody FITC‐E2 by molecular dynamics simulations using various pulling techniques. A large number of long simulations were needed to obtain statistically meaningful results as both the wild type and the H(H58)A mutant unbinding occurs through multiple pathways, often with metastable intermediates. For the wild type, the rate‐limiting step in the unbinding process corresponds to the breaking of the non‐native interactions characteristic of a specific intermediate. The H(H58)A mutation disfavors the occurrence of this intermediate. Two events where the hapten partially unbinds in the absence of pulling force are observed in extensive equilibrium simulations of the wild type, and their analysis indicates that forced unbinding and spontaneous unbinding proceed along similar pathways. The different unbinding mechanisms observed in the simulations suggest a possible reason for the difference in the experimental off‐rate between the two antibodies. We predict mutations that are expected to modulate the occurrence of the unbinding intermediate. For two such new mutants [H(H58)A and S(H52)A], our predictions are validated in silico by additional simulations. The accompanying paper in this issue by Honegger et al. reports the X‐ray structure of FITC‐E2 with a derivative of fluorescein, which was used as the starting conformation for the work presented here.

Bibliography

Curcio, R., Caflisch, A., & Paci, E. (2005). Change of the unbinding mechanism upon a mutation: A molecular dynamics study of an antibodyâhapten complex. Protein Science, 14(10), 2499â2514. Portico.

Authors 3

Raffaele Curcio (first)
Amedeo Caflisch (additional)
Emanuele Paci (additional)

References 44 Referenced 17

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Dates

Type	When
Created	19 years, 11 months ago (Sept. 29, 2005, 6:13 p.m.)
Deposited	1 year, 7 months ago (Jan. 30, 2024, 6:50 a.m.)
Indexed	1 year, 6 months ago (March 4, 2024, 4:01 p.m.)
Issued	19 years, 11 months ago (Oct. 1, 2005)
Published	19 years, 11 months ago (Oct. 1, 2005)
Published Online	16 years, 8 months ago (Jan. 1, 2009)
Published Print	19 years, 11 months ago (Oct. 1, 2005)

Funders 0

None

BibTeX

@article{Curcio_2005, title={Change of the unbinding mechanism upon a mutation: A molecular dynamics study of an antibody–hapten complex}, volume={14}, ISSN={1469-896X}, url={http://dx.doi.org/10.1110/ps.041280705}, DOI={10.1110/ps.041280705}, number={10}, journal={Protein Science}, publisher={Wiley}, author={Curcio, Raffaele and Caflisch, Amedeo and Paci, Emanuele}, year={2005}, month=oct, pages={2499–2514} }

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