Cited by 22Protein Structure and DynamicsLipid Membrane Structure and BehaviorAdvanced Physical and Chemical Molecular Interactions

A Rigorous Framework for Calculating Protein–Protein Binding Affinities in Membranes

Open access
Blazhynska, Marharyta, Gumbart, James C., Chen, Haochuan, Tajkhorshid, Emad, Roux, Benoît, Chipot, Christophe·2023·Journal of Chemical Theory and Computation

Abstract

Calculating the binding free energy of integral transmembrane (TM) proteins is crucial for understanding the mechanisms by which they recognize one another and reversibly associate. The glycophorin A (GpA) homodimer, composed of two α-helical segments, has long served as a model system for studying TM protein reversible association. The present work establishes a methodological framework for calculating the binding affinity of the GpA homodimer in the heterogeneous environment of a membrane. Our investigation carefully considered a variety of protocols, including the appropriate choice of the force field, rigorous standardization reflecting the experimental conditions, sampling algorithm, anisotropic environment, and collective variables, to accurately describe GpA dimerization via molecular dynamics-based approaches. Specifically, two strategies were explored: (i) an unrestrained potential mean force (PMF) calculation, which merely enhances sampling along the separation of the two binding partners without any restraint, and (ii) a so-called "geometrical route", whereby the α-helices are progressively separated with imposed restraints on their orientational, positional, and conformational degrees of freedom to accelerate convergence. Our simulations reveal that the simplified, unrestrained PMF approach is inadequate for the description of GpA dimerization. Instead, the geometrical route, tailored specifically to GpA in a membrane environment, yields excellent agreement with experimental data within a reasonable computational time. A dimerization free energy of -10.7 kcal/mol is obtained, in fairly good agreement with available experimental data. The geometrical route further helps elucidate how environmental forces drive association before helical interactions stabilize it. Our simulations also brought to light a distinct, long-lived spatial arrangement that potentially serves as an intermediate state during dimer formation. The methodological advances in the generalized geometrical route provide a powerful tool for accurate and efficient binding-affinity calculations of intricate TM protein complexes in inhomogeneous environments.

Integrity signals

Registry

Crossref · 10.1021/acs.jctc.3c00941

Cites

160 of 160 references verified0 citation errors · 0 not checkable

Statistics

Recomputing p-values needs the paper’s full text.

Claims the paper makes

We couldn’t retrieve this paper’s full text, so its claims and self-check weren’t run. The registry and citation checks still apply.

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • The protocol has so far been successfully used in calculating the binding free energy of a variety of protein-protein complexes, in good agreement with experimental data, including a homodimeric α-helical complex.

    “The protocol has so far been successfully used in calculating the binding free energy of a variety of protein–protein complexes, in good agreement with experimental data,54,62,64,65,67,73−76 including a homodimeric α-helical complex.69”
  • Since the coiled coils in the present study are all homomultimers composed of identical α-helical monomers, the effect of symmetry must be considered during the calculation of the binding free energy, and a symmetry correction must be applied.

    “Since the coiled coils in the present study are all homomultimers composed of identical α-helical monomers, the effect of symmetry must also be considered during the calculation of the binding free energy.63,69 Therefore, a symmetry correction must be applied to the binding free energy as follows”
  • Simulations without such restraints have been reported to fail to converge and to yield binding free energies inconsistent with experimental data.

    “Simulations without such restraints have been reported to fail to converge and to yield binding free energies inconsistent with experimental data.62,65,69”

Cites

Flagged first, then by citations

Cited by

Sorted by citations

Authors
Blazhynska, M., Gumbart, J. C., Chen, H., Tajkhorshid, E., Roux, B., & Chipot, C.
Affiliations
  • Centre National de la Recherche Scientifique (FR)
  • Georgia Institute of Technology (US)
  • University of Illinois Urbana-Champaign (US)
  • Department of Biochemistry and Molecular Biology, The University of Chicago, 929 E. 57th Street W225, Chicago, Illinois 60637, United States
  • University of Hawaiʻi at Mānoa (US)
Corresponding author
Chipot, Christophe
Venue
Journal of Chemical Theory and Computation
Published
2023-12-13
Volume
19
Issue
24
Pages
9077-9092
ISSN
  • 1549-9618 (ISSN-L)
  • 1549-9626
OpenAlex
W4389656489
Cited by
22
References
160
Citations by year
2026: 8 · 2025: 7 · 2024: 7
FWCI
1.96
Type
journal article
Language
en
Open access
Locations
  • Journal of Chemical Theory and Computation (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
  • HAL (submittedVersion, other-oa)
Funders
  • Agence Nationale de la Recherche
  • National Institute of General Medical Sciences (R01-GM123169, R24-GM145965)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Structure and Dynamics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Lipid Membrane Structure and Behavior
  • Physical Sciences › Chemistry › Physical and Theoretical Chemistry › Advanced Physical and Chemical Molecular Interactions
Keywords
protein-protein binding affinity, transmembrane proteins, glycophorin A, homodimerization, binding free energy, potential of mean force, collective variables, membrane environment
MeSH terms
Membrane Proteins, Protein Binding, Entropy, Dimerization, Molecular Dynamics Simulation

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

Are you an author, or do you see a problem with this page? Request a review