DOE PAGES title logo U.S. Department of Energy
Office of Scientific and Technical Information

Title: Fast antibody fragment motion: flexible linkers act as entropic spring

Abstract

A flexible linker region between three fragments allows antibodies to adjust their binding sites to an antigen or receptor. Using Neutron Spin Echo Spectroscopy we observed fragment motion on a timescale of 7 ns with motional amplitudes of about 1 nm relative to each other. The mechanistic complexity of the linker region can be described by a spring model with Brownian motion of the fragments in a harmonic potential. Displacements, timescale, friction and force constant of the underlying dynamics are accessed. The force constant exhibits a similar strength to an entropic spring, with friction of the fragment matching the unbound state. The observed fast motions are fluctuations in pre-existing equilibrium configurations. In conclusion, the Brownian motion of domains in a harmonic potential is the appropriate model to examine functional hinge motions dependent on the structural topology and highlights the role of internal forces and friction to function.

Authors:
 [1];  [2];  [1];  [3];  [4]
  1. Oak Ridge National Lab. (ORNL), Oak Ridge, TN (United States). Spallation Neutron Source (SNS) and Julich Centre for Neutron Science (JCNS)
  2. Julich Research Centre, Garching (Germany). Julich Centre for Neutron Science (JCNS)
  3. Julich Research Centre and Inst. of Complex Systems, Julich (Germany). Julich Centre for Neutron Science (JCNS)
  4. Julich Research Centre and Inst. of Complex Systems, Julich (Germany). Julich Centre for Neutron Science (JCNS)
Publication Date:
Research Org.:
Oak Ridge National Lab. (ORNL), Oak Ridge, TN (United States)
Sponsoring Org.:
USDOE
OSTI Identifier:
1261399
Grant/Contract Number:  
AC05-00OR22725
Resource Type:
Accepted Manuscript
Journal Name:
Scientific Reports
Additional Journal Information:
Journal Volume: 6; Journal ID: ISSN 2045-2322
Publisher:
Nature Publishing Group
Country of Publication:
United States
Language:
English
Subject:
46 INSTRUMENTATION RELATED TO NUCLEAR SCIENCE AND TECHNOLOGY

Citation Formats

Stingaciu, Laura R., Ivanova, Oxana, Ohl, Michael, Biehl, Ralf, and Richter, Dieter. Fast antibody fragment motion: flexible linkers act as entropic spring. United States: N. p., 2016. Web. doi:10.1038/srep22148.
Stingaciu, Laura R., Ivanova, Oxana, Ohl, Michael, Biehl, Ralf, & Richter, Dieter. Fast antibody fragment motion: flexible linkers act as entropic spring. United States. https://doi.org/10.1038/srep22148
Stingaciu, Laura R., Ivanova, Oxana, Ohl, Michael, Biehl, Ralf, and Richter, Dieter. Tue . "Fast antibody fragment motion: flexible linkers act as entropic spring". United States. https://doi.org/10.1038/srep22148. https://www.osti.gov/servlets/purl/1261399.
@article{osti_1261399,
title = {Fast antibody fragment motion: flexible linkers act as entropic spring},
author = {Stingaciu, Laura R. and Ivanova, Oxana and Ohl, Michael and Biehl, Ralf and Richter, Dieter},
abstractNote = {A flexible linker region between three fragments allows antibodies to adjust their binding sites to an antigen or receptor. Using Neutron Spin Echo Spectroscopy we observed fragment motion on a timescale of 7 ns with motional amplitudes of about 1 nm relative to each other. The mechanistic complexity of the linker region can be described by a spring model with Brownian motion of the fragments in a harmonic potential. Displacements, timescale, friction and force constant of the underlying dynamics are accessed. The force constant exhibits a similar strength to an entropic spring, with friction of the fragment matching the unbound state. The observed fast motions are fluctuations in pre-existing equilibrium configurations. In conclusion, the Brownian motion of domains in a harmonic potential is the appropriate model to examine functional hinge motions dependent on the structural topology and highlights the role of internal forces and friction to function.},
doi = {10.1038/srep22148},
journal = {Scientific Reports},
number = ,
volume = 6,
place = {United States},
year = {Tue Mar 29 00:00:00 EDT 2016},
month = {Tue Mar 29 00:00:00 EDT 2016}
}

Journal Article:
Free Publicly Available Full Text
Publisher's Version of Record

Citation Metrics:
Cited by: 23 works
Citation information provided by
Web of Science

Save / Share:

Works referenced in this record:

The rollercoaster ride to anti-cancer antibodies
journal, May 2003

  • Weiner, Louis M.; Carter, Paul
  • Nature Biotechnology, Vol. 21, Issue 5
  • DOI: 10.1038/nbt0503-510

Small-Angle X-ray Scattering Screening Complements Conventional Biophysical Analysis: Comparative Structural and Biophysical Analysis of Monoclonal Antibodies IgG1, IgG2, and IgG4
journal, June 2014

  • Tian, Xinsheng; Langkilde, Annette E.; Thorolfsson, Matthias
  • Journal of Pharmaceutical Sciences, Vol. 103, Issue 6
  • DOI: 10.1002/jps.23964

Neutron small-angle scattering studies of the general structure of the immunoglobulin G molecule
journal, October 1976


The Solution Structure of Rabbit IgG Accounts for Its Interactions with the Fc Receptor and Complement C1q and Its Conformational Stability
journal, February 2013

  • Rayner, Lucy E.; Kadkhodayi-Kholghi, Nilufar; Heenan, Richard K.
  • Journal of Molecular Biology, Vol. 425, Issue 3
  • DOI: 10.1016/j.jmb.2012.11.019

The solution conformations of the subclasses of human IgG deduced from sedimentation and small angle X-ray scattering studies
journal, August 1987


Structure and Flexibility of Individual Immunoglobulin G Molecules in Solution
journal, March 2004

  • Sandin, Sara; Öfverstedt, Lars-Göran; Wikström, Ann-Charlotte
  • Structure, Vol. 12, Issue 3
  • DOI: 10.1016/j.str.2004.02.011

Immunoglobulin Dynamics, Conformational Fluctuations, and Nonlinear Elasticity and Their Effects on Stability
journal, March 2008

  • Kamerzell, Tim J.; Ramsey, Joshua D.; Middaugh, C. Russell
  • The Journal of Physical Chemistry B, Vol. 112, Issue 10
  • DOI: 10.1021/jp710061a

Emerging Antibody-Based HER2 (ErbB-2/neu) Therapeutics
journal, June 2000

  • Krauss, W. C.; Park, J. W.; Kirpotin, D. B.
  • Breast Disease, Vol. 11, Issue 1
  • DOI: 10.3233/BD-1999-11110

Antibody-targeted radiation cancer therapy
journal, June 2004

  • Milenic, Diane E.; Brady, Erik D.; Brechbiel, Martin W.
  • Nature Reviews Drug Discovery, Vol. 3, Issue 6
  • DOI: 10.1038/nrd1413

Stability of IgG isotypes in serum
journal, May 2010


IgG Subclasses and Allotypes: From Structure to Effector Functions
journal, October 2014


Monomerization of dimeric IgG of intravenous immunoglobulin (IVIg) increases the antibody reactivity against intracellular antigens
journal, May 2008


Segmental flexibility in an antibody molecule
journal, August 1970


Electron microscopy of an antibody-hapten complex
journal, August 1967


The role of the inter-heavy chain disulfide bond in modulating the flexibility of immunoglobulin G antibody
journal, June 1977


Nanosecond fluorescence spectroscopy of pyrenebutyrate-anti-pyrene antibody complexes
journal, August 1977

  • Lovejoy, Charles; Holowka, David A.; Cathou, Renata E.
  • Biochemistry, Vol. 16, Issue 16
  • DOI: 10.1021/bi00635a025

Segmental flexibility of immunoglobulin G antibody molecules in solution: a new interpretation
journal, November 1981

  • Hanson, Douglas C.; Yguerabide, Juan; Schumaker, Verne N.
  • Biochemistry, Vol. 20, Issue 24
  • DOI: 10.1021/bi00527a016

Exploring internal protein dynamics by neutron spin echo spectroscopy
journal, January 2011

  • Biehl, Ralf; Monkenbusch, Michael; Richter, Dieter
  • Soft Matter, Vol. 7, Issue 4
  • DOI: 10.1039/C0SM00683A

Slow internal protein dynamics in solution
journal, November 2014


Large Domain Fluctuations on 50-ns Timescale Enable Catalytic Activity in Phosphoglycerate Kinase
journal, October 2010


Direct Observation of Correlated Interdomain Motion in Alcohol Dehydrogenase
journal, September 2008


Internal Nanosecond Dynamics in the Intrinsically Disordered Myelin Basic Protein
journal, May 2014

  • Stadler, Andreas M.; Stingaciu, Laura; Radulescu, Aurel
  • Journal of the American Chemical Society, Vol. 136, Issue 19
  • DOI: 10.1021/ja502343b

Segmental flexibility in pig immunoglobulin G studied by neutron spin-echo technique
journal, September 1985

  • Alpert, Yolande; Cser, László; Faragó, Béla
  • Biopolymers, Vol. 24, Issue 9
  • DOI: 10.1002/bip.360240908

Influence of the Cosolute Environment on IgG Solution Structure Analyzed by Small-Angle X-ray Scattering
journal, August 2012

  • Lilyestrom, Wayne G.; Shire, Steven J.; Scherer, Thomas M.
  • The Journal of Physical Chemistry B, Vol. 116, Issue 32
  • DOI: 10.1021/jp303839t

Probing antibody internal dynamics with fluorescence anisotropy and molecular dynamics simulations
journal, March 2013

  • Kortkhonjia, Ekaterine; Brandman, Relly; Zhou, Joe Zhongxiang
  • mAbs, Vol. 5, Issue 2
  • DOI: 10.4161/mabs.23651

Dirac–Fock calculations of X-ray scattering factors and contributions to the mean inner potential for electron scattering
journal, July 1994

  • Rez, D.; Rez, P.; Grant, I.
  • Acta Crystallographica Section A Foundations of Crystallography, Vol. 50, Issue 4
  • DOI: 10.1107/S0108767393013200

The Protein Data Bank
journal, January 2000


Analysis of Classical Statistical Mechanics by Means of Collective Coordinates
journal, April 1958


Exact Solution of the Percus-Yevick Integral Equation for Hard Spheres
journal, April 1963


An analytic structure factor for macroion solutions
journal, January 1981


Myoglobin in crowded solutions: structure and diffusion
journal, August 2003


Microscopic Diffusion and Hydrodynamic Interactions of Hemoglobin in Red Blood Cells
journal, August 2007


Reentrant Condensation of Proteins in Solution Induced by Multivalent Counterions
journal, September 2008


Analysis of small angle neutron scattering spectra from polydisperse interacting colloids
journal, September 1983

  • Kotlarchyk, Michael; Chen, Sow‐Hsin
  • The Journal of Chemical Physics, Vol. 79, Issue 5
  • DOI: 10.1063/1.446055

Anatomy of the antibody molecule
journal, February 1994


Structural analysis of a therapeutic monoclonal antibody dimer by hydroxyl radical footprinting
journal, January 2013

  • Deperalta, Galahad; Alvarez, Melissa; Bechtel, Charity
  • mAbs, Vol. 5, Issue 1
  • DOI: 10.4161/mabs.22964

In-depth analysis of subclass-specific conformational preferences of IgG antibodies
journal, January 2015


Intermolecular Interactions of IgG1 Monoclonal Antibodies at High Concentrations Characterized by Light Scattering
journal, October 2010

  • Scherer, Thomas M.; Liu, Jun; Shire, Steven J.
  • The Journal of Physical Chemistry B, Vol. 114, Issue 40
  • DOI: 10.1021/jp1028646

Effect of rotational diffusion on quasielastic light scattering from fractal colloid aggregates
journal, September 1988


The dynamics of interacting Brownian particles
journal, September 1975


Correlations for interacting Brownian particles
journal, January 1976

  • Ackerson, Bruce J.
  • The Journal of Chemical Physics, Vol. 64, Issue 1
  • DOI: 10.1063/1.431957

Many-sphere hydrodynamic interactions and mobilities in a suspension
journal, September 1982


Self-diffusion of spheres in a concentrated suspension
journal, July 1983


Diffusion of spheres in a concentrated suspension II
journal, July 1984


Rotational diffusion in concentrated colloidal dispersions of hard spheres
journal, September 1995

  • Degiorgio, Vittorio; Piazza, Roberto; Jones, Robert B.
  • Physical Review E, Vol. 52, Issue 3
  • DOI: 10.1103/PhysRevE.52.2707

Prediction of Hydrodynamic and Other Solution Properties of Rigid Proteins from Atomic- and Residue-Level Models
journal, August 2011


Crystallographic refinement and atomic models of the intact immunoglobulin molecule Kol and its antigen-binding fragment at 3.0 Å and 1.9 Å resolution
journal, August 1980


On the Theory of the Brownian Motion
journal, September 1930


On the Theory of the Brownian Motion II
journal, April 1945


Quasielastic neutron scattering and relaxation processes in proteins: analytical and simulation-based models
journal, January 2005

  • Kneller, Gerald R.
  • Physical Chemistry Chemical Physics, Vol. 7, Issue 13
  • DOI: 10.1039/b502040a

Large Amplitude Elastic Motions in Proteins from a Single-Parameter, Atomic Analysis
journal, August 1996


The study of protein mechanics with the atomic force microscope
journal, October 1999

  • Fisher, Thomas E.; Oberhauser, Andres F.; Carrion-Vazquez, Mariano
  • Trends in Biochemical Sciences, Vol. 24, Issue 10
  • DOI: 10.1016/S0968-0004(99)01453-X

Contrasting IgG Structures Reveal Extreme Asymmetry and Flexibility
journal, May 2002

  • Saphire, Erica Ollmann; Stanfield, Robyn L.; Max Crispin, M. D.
  • Journal of Molecular Biology, Vol. 319, Issue 1
  • DOI: 10.1016/S0022-2836(02)00244-9

A Theory of the Structure and Process of Formation of Antibodies *
journal, October 1940

  • Pauling, Linus
  • Journal of the American Chemical Society, Vol. 62, Issue 10
  • DOI: 10.1021/ja01867a018

Inelastic neutron scattering from damped collective vibrations of macromolecules
journal, November 2000


The molecular modeling toolkit: A new approach to molecular simulations
journal, January 2000


Harmonicity in slow protein dynamics
journal, November 2000


Works referencing / citing this record:

Dual entropic and enthalpic processes in the lower critical solution temperature phase separation of poly(vinyl methyl ether) aqueous solutions
journal, January 2019

  • Song, Li; Lin, Jiaxiang; He, Yang
  • Journal of Polymer Science Part B: Polymer Physics, Vol. 57, Issue 6
  • DOI: 10.1002/polb.24788

Dynamics of proteins in solution
journal, January 2019


Transition between protein-like and polymer-like dynamic behavior: Internal friction in unfolded apomyoglobin depends on denaturing conditions
journal, January 2020