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

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 $α_Vβ_3$. 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.