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Two-dimensional structures of DNA aptamers adopted in this work. The structures were predicted by mfold (ref. 22). The elongated or mutated residues are marked in red
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Vascular endothelial growth factor 165 (VEGF165), a predominant isoform of VEGF signal proteins, is an ideal target for developing drugs against various diseases. It is composed of a heparin binding domain (HBD) and a receptor binding domain (RBD), which are connected by a flexible linker. Among the two domains, RBD is utilized in binding with the...
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... In this paper, we study two aptamer heterodimers, RNV66:del5-1 and V7t1:del5-1, as well as three monomeric aptamers, RNV66, V7t1, and del5-1, for targeting VEGF165. Through computational means, we tried to incorporate small-and large-scale motions into the consideration of the protein-aptamer interaction [39] involving VEGF165. ...
... For the protein side, the full experimental structure of the homodimeric VEGF165 is not available. However, the X-ray crystal structure of the homodimeric RBD (PDB ID: 2VPF) [10] and the NMR structure of the monomeric HBD (PDB ID: 1VGH) [9] are available, and we manually linked HBD to each RBD monomer using the sequence information [8,39]. The interdomain linker sequence was RPKKDRARQENP, where RPKKD and ARQENP corresponded to the X-ray crystal structure of RBD (PDB ID: 2VPF) and the NMR structure of HBD (PDB ID: 1VGH), respectively. ...
Vascular endothelial growth factor 165 (VEGF165) is a prominent isoform of the VEGF-A protein that plays a crucial role in various angiogenesis-related diseases. It is homodimeric, and each of its monomers is composed of two domains connected by a flexible linker. DNA aptamers, which have emerged as potent therapeutic molecules for many proteins with high specificity and affinity, can also work for VEGF165. A DNA aptamer heterodimer composed of monomers of V7t1 and del5-1 connected by a flexible linker (V7t1:del5-1) exhibits a greater binding affinity with VEGF165 compared to either of the two monomers alone. Although the structure of the complex formed between the aptamer heterodimer and VEGF165 is unknown due to the highly flexible linkers, gaining structural information will still be valuable for future developments. Toward this end of accessing structural information, we adopt an ensemble docking approach here. We first obtain an ensemble of structures for both VEGF165 and the aptamer heterodimer by considering both small- and large-scale motions. We then proceed through an extraction process based on ensemble docking, molecular dynamics simulations, and binding free energy calculations to predict the structures of the VEGF165/V7t1:del5-1 complex. Through the same procedures, we reach a new aptamer heterodimer that bears a locked nucleic acid-modified counterpart of V7t1, namely RNV66:del5-1, which also binds well with VEGF165. We apply the same protocol to the monomeric units V7t1, RNV66, and del5-1 to target VEGF165. We observe that V7t1:del5-1 and RNV66:del5-1 show higher binding affinities with VEGF165 than any of the monomers, consistent with experiments that support the notion that aptamer heterodimers are more effective anti-VEGF165 aptamers than monomeric aptamers. Among the five different aptamers studied here, the newly designed RNV66:del5-1 shows the highest binding affinity with VEGF165. We expect that our ensemble docking approach can help in de novo designs of homo/heterodimeric anti-angiogenic drugs to target the homodimeric VEGF165.
Macugen is a therapeutic RNA aptamer against vascular endothelial growth factor (VEGF)-165, the VEGF isoform primarily responsible for angiogenesis. It has been reported that Macugen inhibits angiogenesis by specifically binding to the heparin binding domain (HBD) of VEGF165. The mechanism of the molecular recognition between HBD and Macugen is investigated here using all-atom molecular dynamics simulations. We find that Macugen recognizes HBD by an induced-fit mechanism with major conformational changes in Macugen and almost no changes in the structure of HBD, whereas HBD recognizes Macugen by a conformational selection mechanism.
