Determining the Optimal Heparin Binding Domain Distance in VEGF₁₆₅ Using Umbrella Sampling Simulations for Optimal...

Area of Science:

• Biochemistry and Molecular Biology
• Biophysics
• Drug Discovery

Background:

• Vascular endothelial growth factor 165 (VEGF165) is crucial in angiogenesis-related diseases and a therapeutic target.
• VEGF165 structure, with its receptor-binding (RBD) and heparin-binding (HBD) domains, is not fully understood.
• Dimeric aptamers targeting VEGF165 show promise but require optimized linker lengths for enhanced potency.

Purpose of the Study:

• To elucidate the structural dynamics of VEGF165, specifically the distance between its heparin-binding domains (HBDs).
• To provide quantitative insights for designing high-affinity aptamer dimers targeting VEGF165.
• To establish guidelines for optimizing linker lengths in aptamer-based therapeutics.

Main Methods:

• Biased molecular dynamics (MD) simulations utilizing the umbrella sampling method.
• Employing the distance between the two HBDs as the reaction coordinate.
• Computational design of aptamer homodimers with varying linker lengths.

Main Results:

• VEGF165 exhibits a preference for compact conformations, with optimal HBD-HBD distances below 3 nm, and a potential of mean force minimum at 1.1 nm.
• The optimal HBD-HBD distance facilitates key hydrogen bond formation between VEGF165 and its receptor VEGFR-2.
• Computational design explored aptamer homodimers targeting VEGF165, providing data on linker length effects.

Conclusions:

• The study provides crucial distance information for VEGF165 structure, aiding in understanding its interactions.
• Findings offer quantitative guidelines for the rational design of potent aptamer dimers targeting VEGF165.
• This research contributes to the development of novel aptamer-based diagnostics and therapeutics for angiogenesis-related diseases.