DOI: 10.1126/science.271.5251.997. Ligand Binding: Molecular Mechanics Calculation of the Streptavidin-Biotin Rupture Force

Ligand Binding: Molecular Mechanics Calculation of the Streptavidin-Biotin Rupture Force

10.1126/science.271.5251.997

Crossref journal-article

American Association for the Advancement of Science (AAAS)

Science (221)

Abstract

The force required to rupture the streptavidin-biotin complex was calculated here by computer simulations. The computed force agrees well with that obtained by recent single molecule atomic force microscope experiments. These simulations suggest a detailed multiple-pathway rupture mechanism involving five major unbinding steps. Binding forces and specificity are attributed to a hydrogen bond network between the biotin ligand and residues within the binding pocket of streptavidin. During rupture, additional water bridges substantially enhance the stability of the complex and even dominate the binding interactions. In contrast, steric restraints do not appear to contribute to the binding forces, although conformational motions were observed.

Bibliography

GrubmÃ¼ller, H., Heymann, B., & Tavan, P. (1996). Ligand Binding: Molecular Mechanics Calculation of the Streptavidin-Biotin Rupture Force. Science, 271(5251), 997â999.

Authors 3

Helmut Grubmüller (first)
Berthold Heymann (additional)
Paul Tavan (additional)

References 23 Referenced 816

BROOKS R. B., CHARMM - A PROGRAM FOR MACROMOLECULAR ENERGY, MINIMIZATION, AND DYNAMICS CALCULATIONS, JOURNAL OF COMPUTATIONAL CHEMISTRY 4, 187 (1983). (10.1002/jcc.540040211) / JOURNAL OF COMPUTATIONAL CHEMISTRY / CHARMM - A PROGRAM FOR MACROMOLECULAR ENERGY, MINIMIZATION, AND DYNAMICS CALCULATIONS by BROOKS R. B. (1983)
BROOKS L. C., DEFORMABLE STOCHASTIC BOUNDARIES IN MOLECULAR-DYNAMICS, JOURNAL OF CHEMICAL PHYSICS 79, 6312 (1983). (10.1063/1.445724) / JOURNAL OF CHEMICAL PHYSICS / DEFORMABLE STOCHASTIC BOUNDARIES IN MOLECULAR-DYNAMICS by BROOKS L. C. (1983)
BRUNGER T. A., X PLOR (1988). / X PLOR by BRUNGER T. A. (1988)
EICHINGER M, E COMMUNICATION (1995). / E COMMUNICATION by EICHINGER M (1995)
EICHINGER M unpublished data.
ELBER R, IN PRESS NEW DEV THE . / IN PRESS NEW DEV THE by ELBER R
10.1126/science.8153628
FRAUENFELDER H, TEMPERATURE-DEPENDENT X-RAY-DIFFRACTION AS A PROBE OF PROTEIN STRUCTURAL DYNAMICS, NATURE 280, 558 (1979). (10.1038/280558a0) / NATURE / TEMPERATURE-DEPENDENT X-RAY-DIFFRACTION AS A PROBE OF PROTEIN STRUCTURAL DYNAMICS by FRAUENFELDER H (1979)
GREEN M. N., ADV PROTEIN CHEM 29, 85 (1975). (10.1016/S0065-3233(08)60411-8) / ADV PROTEIN CHEM by GREEN M. N. (1975)
GRUBMULLER H, PREDICTING SLOW STRUCTURAL TRANSITIONS IN MACROMOLECULAR SYSTEMS - CONFORMATIONAL FLOODING, PHYSICAL REVIEW E 52, 2893 (1995). (10.1103/PhysRevE.52.2893) / PHYSICAL REVIEW E / PREDICTING SLOW STRUCTURAL TRANSITIONS IN MACROMOLECULAR SYSTEMS - CONFORMATIONAL FLOODING by GRUBMULLER H (1995)
HELLER H, MOL SIMULAT 5, 133 (1990). (10.1080/08927029008022127) / MOL SIMULAT by HELLER H (1990)
JORGENSON L. W., J CHEM PHYS 79, 927 (1983). / J CHEM PHYS by JORGENSON L. W. (1983)
KITAO A, EFFECTS OF SOLVENT ON THE CONFORMATION AND THE COLLECTIVE MOTIONS OF A PROTEIN .2. STRUCTURE OF HYDRATION IN MELITTIN, JOURNAL OF PHYSICAL CHEMISTRY 97, 10223 (1993). (10.1021/j100141a052) / JOURNAL OF PHYSICAL CHEMISTRY / EFFECTS OF SOLVENT ON THE CONFORMATION AND THE COLLECTIVE MOTIONS OF A PROTEIN .2. STRUCTURE OF HYDRATION IN MELITTIN by KITAO A (1993)
10.1107/S0021889891004399
LEE U. G., SENSING DISCRETE STREPTAVIDIN BIOTIN INTERACTIONS WITH ATOMIC-FORCE MICROSCOPY, LANGMUIR 10, 354 (1994). (10.1021/la00014a003) / LANGMUIR / SENSING DISCRETE STREPTAVIDIN BIOTIN INTERACTIONS WITH ATOMIC-FORCE MICROSCOPY by LEE U. G. (1994)
LIVNAH O, 3-DIMENSIONAL STRUCTURES OF AVIDIN AND THE AVIDIN-BIOTIN COMPLEX, PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA 90, 5076 (1993). (10.1073/pnas.90.11.5076) / PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA / 3-DIMENSIONAL STRUCTURES OF AVIDIN AND THE AVIDIN-BIOTIN COMPLEX by LIVNAH O (1993)
MCCAMMON A. J., DYNAMICS OF FOLDED PROTEINS, NATURE 267, 585 (1977). (10.1038/267585a0) / NATURE / DYNAMICS OF FOLDED PROTEINS by MCCAMMON A. J. (1977)
MIYAMOTO S, ABSOLUTE AND RELATIVE BINDING FREE-ENERGY CALCULATIONS OF THE INTERACTION OF BIOTIN AND ITS ANALOGS WITH STREPTAVIDIN USING MOLECULAR-DYNAMICS FREE-ENERGY PERTURBATION APPROACHES, PROTEINS-STRUCTURE FUNCTION AND BIOINFORMATICS 16, 226 (1993). (10.1002/prot.340160303) / PROTEINS-STRUCTURE FUNCTION AND BIOINFORMATICS / ABSOLUTE AND RELATIVE BINDING FREE-ENERGY CALCULATIONS OF THE INTERACTION OF BIOTIN AND ITS ANALOGS WITH STREPTAVIDIN USING MOLECULAR-DYNAMICS FREE-ENERGY PERTURBATION APPROACHES by MIYAMOTO S (1993)
10.1126/science.7939660
NIEDERMEIER C, A STRUCTURE ADAPTED MULTIPOLE METHOD FOR ELECTROSTATIC INTERACTIONS IN PROTEIN DYNAMICS, JOURNAL OF CHEMICAL PHYSICS 101, 734 (1994). (10.1063/1.468129) / JOURNAL OF CHEMICAL PHYSICS / A STRUCTURE ADAPTED MULTIPOLE METHOD FOR ELECTROSTATIC INTERACTIONS IN PROTEIN DYNAMICS by NIEDERMEIER C (1994)
VANGUNSTEREN F. W., ALGORITHMS FOR MACROMOLECULAR DYNAMICS AND CONSTRAINT DYNAMICS, MOLECULAR PHYSICS 34, 1311 (1977). (10.1080/00268977700102571) / MOLECULAR PHYSICS / ALGORITHMS FOR MACROMOLECULAR DYNAMICS AND CONSTRAINT DYNAMICS by VANGUNSTEREN F. W. (1977)
WEBER C. P., CRYSTALLOGRAPHIC AND THERMODYNAMIC COMPARISON OF NATURAL AND SYNTHETIC LIGANDS BOUND TO STREPTAVIDIN, JOURNAL OF THE AMERICAN CHEMICAL SOCIETY 114, 3197 (1992). (10.1021/ja00035a004) / JOURNAL OF THE AMERICAN CHEMICAL SOCIETY / CRYSTALLOGRAPHIC AND THERMODYNAMIC COMPARISON OF NATURAL AND SYNTHETIC LIGANDS BOUND TO STREPTAVIDIN by WEBER C. P. (1992)
10.1126/science.2911722

Dates

Type	When
Created	18 years, 10 months ago (Oct. 27, 2006, 2:30 p.m.)
Deposited	1 year, 7 months ago (Jan. 12, 2024, 4:10 p.m.)
Indexed	1 day, 6 hours ago (Aug. 31, 2025, 6:33 a.m.)
Issued	29 years, 6 months ago (Feb. 16, 1996)
Published	29 years, 6 months ago (Feb. 16, 1996)
Published Print	29 years, 6 months ago (Feb. 16, 1996)

Funders 0

None

BibTeX

@article{Grubm_ller_1996, title={Ligand Binding: Molecular Mechanics Calculation of the Streptavidin-Biotin Rupture Force}, volume={271}, ISSN={1095-9203}, url={http://dx.doi.org/10.1126/science.271.5251.997}, DOI={10.1126/science.271.5251.997}, number={5251}, journal={Science}, publisher={American Association for the Advancement of Science (AAAS)}, author={Grubmüller, Helmut and Heymann, Berthold and Tavan, Paul}, year={1996}, month=feb, pages={997–999} }

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