Intermolecular Pose Exploration using Subdivided Spheres

Abstract

We present a new method to evaluate the two-body partition function and related thermodynamic properties using a discrete grid of angles between molecular bodies. The method, based on subdivided spheres, is applied to protein-protein interactions, which depend on their separation, as well as relative orientations. Orientational dependence is due to force anisotropies, which are reflected in thermody- namic quantities. Non-monotonic variations, with both ionic strength and temperature, are shown for the osmotic second virial coefficient (B2); a widely used metric for assessing protein stability in pharmaceutical formulations. Variations of the Calvados3 force-field were applied on α-Chymotrypsinogen A, “Cgn”, showing that to capture the non-monotonic variations at low salt, the amino acid charges have to be placed off-center. This correction renders results matching presented experimental data, see Fig. 3. A principal component analysis (PCA) found configurational clusters at free energy minima, some of which we could match to empirical structures. The method is implemented in an open source computa- tional tool, Duello, for analyzing arbitrary molecules, including globular proteins. Our technique systematically explores and discretizes angular space on a nearly spherically-uniform grid, enabling efficient calculations of the two-body partition function and, subsequently, all related thermodynamic quantities. Where available, excellent agreement is found with experiment and exact numerical simulations.

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BibTeX RIS

BibTeX

@article{vinterbladh2026intermolecular,
  title = {{Intermolecular Pose Exploration using Subdivided Spheres}},
  author = {Isabel Vinterbladh and Jordan Bye and Robin Curtis and Harold W. Hatch and Sergei Grudinin and Mikael Lund},
  journal = {Journal of Physical Chemistry B},
  year = {2026},
  month = jun,
  doi = {10.1021/acs.jpcb.6c01665},
  url = {https://hal.science/hal-05337856v2},
  note = {CC BY 4.0},
}

RIS

TY  - JOUR
TI  - Intermolecular Pose Exploration using Subdivided Spheres
AU  - Isabel Vinterbladh
AU  - Jordan Bye
AU  - Robin Curtis
AU  - Harold W. Hatch
AU  - Sergei Grudinin
AU  - Mikael Lund
PY  - 2026
DA  - 2026/06/09
JO  - Journal of Physical Chemistry B
DO  - 10.1021/acs.jpcb.6c01665
UR  - https://hal.science/hal-05337856v2
AB  - We present a new method to evaluate the two-body partition function and related thermodynamic properties using a discrete grid of angles between molecular bodies. The method, based on subdivided spheres, is applied to protein-protein interactions, which depend on their separation, as well as relative orientations. Orientational dependence is due to force anisotropies, which are reflected in thermody- namic quantities. Non-monotonic variations, with both ionic strength and temperature, are shown for the osmotic second virial coefficient (B2); a widely used metric for assessing protein stability in pharmaceutical formulations. Variations of the Calvados3 force-field were applied on α-Chymotrypsinogen A, “Cgn”, showing that to capture the non-monotonic variations at low salt, the amino acid charges have to be placed off-center. This correction renders results matching presented experimental data, see Fig. 3. A principal component analysis (PCA) found configurational clusters at free energy minima, some of which we could match to empirical structures. The method is implemented in an open source computa- tional tool, Duello, for analyzing arbitrary molecules, including globular proteins. Our technique systematically explores and discretizes angular space on a nearly spherically-uniform grid, enabling efficient calculations of the two-body partition function and, subsequently, all related thermodynamic quantities. Where available, excellent agreement is found with experiment and exact numerical simulations.
SN  - 1520-6106
SN  - 1520-5207
ER  -

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