Abstract
Glycoprotein (GP: HIS1-PRO265) Ibɑ is a receptor protein expressed on the surface of the platelet. Its N-terminus
domain binds with the A1 domain (ASP1269-PRO1472) of its ligand protein von Willebrand factor (VWF) and plays a unique role in platelet
adhesion under blood flow conditions. Single amino acid substitutions at residue 233
from glycine (G) to alanine (A), aspartic acid (D), or valine (V) are known to cause
biochemically distinct functional alterations known as equal, loss, and gain of function,
respectively. However, the underlying physical characteristics of VWF binding with
GPIbɑ in wild-type and the three mutants exerting different biological functions are
unclear. Here, we aimed to test the hypothesis: biological characteristics of macromolecules
are influenced by small changes in physical parameters. The position coordinates and
velocity vectors of all atoms and water molecules constructing the wild-type and the
three mutants of GPIbɑ (G233A, G233D, and G233V) bound with VWF were calculated every
2 × 10−15 seconds using the CHARMM (Chemistry at Harvard Macromolecular Mechanics) force field
for 9 × 10−10 seconds. Six salt bridges were detected for longer than 50% of the calculation period
for the wild-type model generating noncovalent binding energy of −1096 ± 137.6 kcal/mol.
In contrast, only four pairs of salt bridges were observed in G233D mutant with noncovalent
binding energy of −865 ± 139 kcal/mol. For G233A and G233V, there were six and five
pairs of salt bridges generating −929.8 ± 88.5 and −989.9 ± 94.0 kcal/mol of noncovalent
binding energy, respectively. Our molecular dynamic simulation showing a lower probability
of salt bridge formation with less noncovalent binding energy in VWF binding with
the biologically loss of function G233D mutant of GPIbɑ as compared with wild-type,
equal function, and gain of function mutant suggests that biological functions of
macromolecules such as GPIbɑ are influenced by their small changes in physical characteristics.
Keywords
platelet - von Willebrand factor - salt bridge - molecular dynamic
