Design single-stranded DNA aptamer of cluster of differentiation 47 protein by stochastic tunnelling-basin hopping-discrete molecular dynamics method

The formation of the Cluster of Differentiation 47 (CD47, PDB code: 2JJT)/signal regulatory protein α (SIRPα) complex is very important as it protects healthy cells from immune clearance while promoting macrophage phagocytosis for tumour elimination. Although several antibodies have been developed for cancer therapy, new function-blocking aptamers are still under development. This study aims to design the aptamer Apt_CD47, which can block the formation of the CD47/SIRPα complex. This study employs the MARTINI coarse-grained (CG) force field and the stochastic tunnelling-basin hopping-discrete molecular dynamics (STUN-BH-DMD) method to identify the most stable Apt_CD47/CD47 complexes. Coarse-grained molecular dynamics (CGMD) simulations were used to obtain root-mean-square deviation (RMSD) and root-mean-square fluctuation (RMSF) analyses. The results demonstrate that the formation of Apt_CD47/CD47 complexes renders the CD47 structure more stable than the single CD47 molecule in a water environment. The minimum energy pathway (MEP) obtained by the nudged elastic band (NEB) method indicates that the binding processes of 5′-ATTCAATTCC-3′ and 5′-AGTGCAATCT-3′ to CD47 are barrierless, which is much lower than the binding barrier of SIRPα to CD47 of about 14.23 kcal/mol. Therefore, these two Apt_CD47/CD47 complexes can create a high spatial binding barrier for SIRPα, preventing the formation of a stable CD47/SIRPα complex. The proposed numerical process with the MARTINI CG force field can be used to design CD47 aptamers that efficiently block SIRPα from binding to CD47. Communicated by Ramaswamy H. Sarma.