Predicted destabilization of interdomain interaction in the ^ALA284-^ARG531-^ARG282 region.

(A) Close-up view of a portion of the A1-A2 interdomain boundary in the FVIII A domain model, showing the putative interaction of the^ARG531 side chain with the main chain carbonyl of^ARG282, together with the close packing of the^ALA284 side chain against that of ^ARG531. Replacement of the Ala side chain by the bulky polar Glu side chain (as in the hemophilia A variant ^ALA284^GLU) is predicted to disturb the ^ARG282-^ARG531 interaction. Side chains are colored by atom (C, green; O, red; N, blue; H, white). (B) Predicted destabilization of interdomain interaction in the ^SER289-^TYR1979 region. Close-up view of a portion of the A1-A3 interdomain boundary, showing the putative interaction of the ^SER289 side chain with the side chain of ^TYR1979. Replacement of the Ser side chain by the bulky hydrophobic Leu side chain (as in the hemophilia A variant^SER289^LEU) is predicted to disturb the^SER289-^TYR1979 interaction and packing of surrounding residues. Side chains are colored by atom (C, green; O, red; N, blue; H, white).