ABSTRACT
The vascular endothelial growth factor (VEGF) seems to be the most important regulator of physiological and pathological angiogenesis, being, for this reason, a favorite target for therapies against angiogenesis-related diseases. VEGF is a homodimer in which the monomers are formed by beta-strands interconnected on the poles by three loops. A recent work showed that an intimate relationship between loops-1 and -3 is required for high affinity binding to the receptors (Kiba et al., J Biol Chem 2003;278:13453-13461). In this work, we report the results of a 10-ns molecular dynamics simulation of VEGF. We analyzed the dynamical behavior of the protein (using a dynamical cross-correlation map) and found that it is governed by a high degree of correlation between the motions of the loops. We also performed a principal component analysis and found an overall motion in which the opposite poles are projected against each other, just like the movement of the wings of a butterfly. From the biological point of view, it is likely that this motion would facilitate receptor binding since VEGF must enter a restricted cavity formed by the two subunits of the receptor.
