RAD51 is a central component of homologous recombination, whose activity is tightly regulated by interactions with DNA and several protein partners, including BRCA2.[1] Its structural plasticity plays an important role in these interactions, while the RAD51–BRCA2 interface also represents an attractive opportunity for pharmacological modulation.[2] Here, we present different computational approaches to investigate the structural and conformational landscape of human RAD51. Molecular dynamics simulations were used to study small-molecule recognition, focusing on the effect of different ligand tautomeric states and on conformational changes associated with compounds showing different effects on homologous recombination. In parallel, experimental RAD51 structures and conformations from a previously generated RAD51–BRC4 ensemble[3] were analyzed to identify unexplored binding pockets. Selected sites were investigated through virtual screening, induced-fit docking, and molecular dynamics simulations. Finally, building on recent structural studies of RAD51–BRC repeat complexes,[4] we are developing a metainference approach combining molecular dynamics with experimental restraints to reconstruct conformational ensembles of RAD51 bound to different BRCA2 BRC repeats. Altogether, these studies provide a broader view of RAD51 conformational dynamics, linking its interactions with small molecules and BRCA2 to the identification of new opportunities for pharmacological modulation. References 1) R. B. Jensen, A. Carreira, S. C. Kowalczykowski, Nature, 467, 678–683 (2010). 2) G. Bagnolini, D. Milano, M. Manerba, F. Schipani, J. A. Ortega, D. Gioia, F. Falchi, A. Balboni, F. Farabegoli, F. De Franco, J. Robertson, R. Pellicciari, I. Pallavicini, S. Peri, S. Minucci, S. Girotto, G. Di Stefano, M. Roberti, A. Cavalli, J. Med. Chem., 63, 2588–2619 (2020). 3) V. Bresciani, F. Rinaldi, P. Franco, et al., J. Chem. Inf. Model., 65, 11965–11978 (2025). 4) F. Rinaldi, P. Franco, M. Veronesi, et al., bioRxiv, 2025.11.13.688182 (2025).
Bosio, S., Freccia, A., Masi, M., Rinaldi, F., Girotto, S., Falchi, F., et al. (2026). Exploring RAD51 structural plasticity through molecular simulations and integrative structural biology.
Exploring RAD51 structural plasticity through molecular simulations and integrative structural biology
Bosio S.Primo
;Rinaldi F.;Falchi F.;Cavalli A.
Ultimo
2026
Abstract
RAD51 is a central component of homologous recombination, whose activity is tightly regulated by interactions with DNA and several protein partners, including BRCA2.[1] Its structural plasticity plays an important role in these interactions, while the RAD51–BRCA2 interface also represents an attractive opportunity for pharmacological modulation.[2] Here, we present different computational approaches to investigate the structural and conformational landscape of human RAD51. Molecular dynamics simulations were used to study small-molecule recognition, focusing on the effect of different ligand tautomeric states and on conformational changes associated with compounds showing different effects on homologous recombination. In parallel, experimental RAD51 structures and conformations from a previously generated RAD51–BRC4 ensemble[3] were analyzed to identify unexplored binding pockets. Selected sites were investigated through virtual screening, induced-fit docking, and molecular dynamics simulations. Finally, building on recent structural studies of RAD51–BRC repeat complexes,[4] we are developing a metainference approach combining molecular dynamics with experimental restraints to reconstruct conformational ensembles of RAD51 bound to different BRCA2 BRC repeats. Altogether, these studies provide a broader view of RAD51 conformational dynamics, linking its interactions with small molecules and BRCA2 to the identification of new opportunities for pharmacological modulation. References 1) R. B. Jensen, A. Carreira, S. C. Kowalczykowski, Nature, 467, 678–683 (2010). 2) G. Bagnolini, D. Milano, M. Manerba, F. Schipani, J. A. Ortega, D. Gioia, F. Falchi, A. Balboni, F. Farabegoli, F. De Franco, J. Robertson, R. Pellicciari, I. Pallavicini, S. Peri, S. Minucci, S. Girotto, G. Di Stefano, M. Roberti, A. Cavalli, J. Med. Chem., 63, 2588–2619 (2020). 3) V. Bresciani, F. Rinaldi, P. Franco, et al., J. Chem. Inf. Model., 65, 11965–11978 (2025). 4) F. Rinaldi, P. Franco, M. Veronesi, et al., bioRxiv, 2025.11.13.688182 (2025).I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
