Limitations of Classical Force Fields for Metal Coordination Modes in Proteins: A Multilevel Study of Ca$^{2+}$ in Integrin $α_Vβ_3$

Levy Andrea; Frigerio Giulia; Grollier Jules; Siani Paulo; Di Valentin Cristiana; Rothlisberger Ursula

Limitations of Classical Force Fields for Metal Coordination Modes in Proteins: A Multilevel Study of Ca$^{2+}$ in Integrin $α_Vβ_3$

Chemical Physics 2026-06-26 v1

Authors: Levy Andrea , Frigerio Giulia , Grollier Jules , Siani Paulo , Di Valentin Cristiana , Rothlisberger Ursula

Abstract

Standard biomolecular force fields often present limitations in modeling metal coordination modes. Here, we combined classical and QM/MM molecular dynamics simulations to investigate the Ca $^{2+}$ mediated binding of cRGD to integrin $\alpha_V\beta_3$ . The results demonstrate the inherent limitations of fixed-point-charge force fields in reproducing asymmetric binding modes and highlight the value of QM-based multilevel approaches to assess the correctness and accuracy of FF models and capture metal coordination modes in complex biomolecular systems.

Keywords

force fields metal coordination QM/MM molecular dynamics integrin calcium binding

Cite

@article{arxiv.2606.28463,
  title  = {Limitations of Classical Force Fields for Metal Coordination Modes in Proteins: A Multilevel Study of Ca$^{2+}$ in Integrin $α_Vβ_3$},
  author = {Levy Andrea and Frigerio Giulia and Grollier Jules and Siani Paulo and Di Valentin Cristiana and Rothlisberger Ursula},
  journal= {arXiv preprint arXiv:2606.28463},
  year   = {2026}
}