Molecular modeling of the von Willebrand factor A2 Domain and the effects of associated type 2A von Willebrand disease mutations

• Published in: Journal of molecular modeling 2004-08, Vol.10 (4), p.259-270
• Main Authors: Sutherland, Jeffrey J, O'Brien, Lee A, Lillicrap, David, Weaver, Donald F
• Format: Article
• Language: English
• Subjects: Amino Acid Sequence; Amino Acid Substitution; Computer Simulation; Genetic Predisposition to Disease; Models, Molecular; Molecular Sequence Data; Mutation; Protein Structure, Tertiary; Sequence Alignment; Structural Homology, Protein; von Willebrand Diseases - genetics; von Willebrand Factor - chemistry; von Willebrand Factor - genetics
• ISSN: 1610-2940; 0948-5023
• DOI: 10.1007/s00894-004-0194-9

A homology model for the A2 domain of von Willebrand factor (VWF) is presented. A large number of target-template alignments were combined into a consensus alignment and used for constructing the model from the structures of six template proteins. Molecular dynamics simulation was used to study the structural and dynamic effects of eight mutations introduced into the model, all associated with type 2A von Willebrand disease. It was found that the group I mutations G1505R, L1540P and S1506L cause significant deviations over multiple regions of the protein, coupled to significant thermal fluctuations for G1505R and L1540P. This suggests that protein instability may be responsible for their intracellular retention. The group II mutations R1597W, E1638K and G1505E caused single loop displacements near the physiologic VWF proteolysis site between Y1605-M1606. These modest structural changes may affect interactions between VWF and the ADAMTS13 protease. The group II mutations I1628T and L1503Q caused no significant structural change in the protein, suggesting that inclusion of the protease in this model is necessary for understanding their effect. [Figure: see text]. Homology model of the von Willebrand factor A2 domain