Speaker
Description
Biomolecular simulations have long been an important part of the drug discovery and development process, with techniques such as docking, virtual screening, molecular dynamics and quantum mechanics being routinely used in the study of the interaction and selection of small molecular drugs with their target proteins or enzymes.
More recently, the application of these techniques in aptamer selection and aptamer engineering has algo become a reality. Such methods can help to understand aptamer-target interaction and to rationally introduce modifications in selected aptamers to modulate their affinity, specificity or ability to carry other molecules.
Here, we present a computational protocol developed by us for the selection of specific aptamers for protein recognition and for an atomic-level understanding of target-aptamer interaction. The protocol takes advantage of HPC resources and GPUs and combines protein-DNA/RNA docking, atomistic molecular dynamics simulations and free energy calculations, including the conformation variability of the protein and aptamer in the selection process.
This is illustrated with the identification and experimental confirmation of a novel aptamer for Cathepsin B, a predictive prostate cancer biomarker [1], and by atomic level clarification of the mode of action of an aptamer-RNA conjugate that targets the human transferrin receptor [2].
Acknowledgements: This work received financial support from FCT/MCTES (UIDB/50006/2020 DOI 10.54499/UIDB/50006/2020) through national funds. This work received support and help from FCT/MCTES (LA/P/0008/2020 DOI 10.54499/LA/P/0008/2020, UIDP/50006/2020 DOI 10.54499/UIDP/50006/2020 and UIDB/50006/2020 DOI 10.54499/UIDB/50006/2020), through national funds. The author acknowledges FCT by funding 2020.01423.CEECIND/CP1596/CT0003. Calculations were performed with the support of INCD funded by FCT projects 01/SAICT/2016 number 022153, and projects CPCA/A00/7140/2020, and CPCA/A00/7145/2020.
References:
[1] Pereira, AC et al. - Identification of novel aptamers targeting cathepsin B-overexpressing prostate cancer cells - Molecular Systems Design & Engineering (2022) DOI: 10.1039/D2ME00022A
[2] Vasconcelos et al. -In silico analysis of aptamer-RNA conjugate interactions with human transferrin receptor - Biophysical Chemistry 314 (2024, DOI: 10.1016/j.bpc.2024.107308
