Modeling the intact form of the α1-proteinase inhibitor

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Abstract
The structure of the intact form of the serpin α1-proteinase inhibitor has been modeled based on the assumption that the central strand s4A of the six-stranded β-sheet A of the cleaved inhibitor is not incorporated into the sheet of intact α1-proteinase inhibitor. This strand was removed from its position in the center of the sheet by suitable rotations about the backbone dihedrals of Lys343 using molecular graphics. The resulting structure was then annealed using molecular dynamics (MD) while applying progressive distance restraints to the reactive peptide bond (Met358-Ser359) for 50 ps. During this time, the disrupted β-sheet reformed to create a five-stranded β-sheet with strands 3 and 5 in a parallel arrangement. This change and accompanying structural rearrangements are largely confirmed by the X-ray structure of plakalbumin, whose structure reflects the overall structure of intact serpins. The successful modeling experiment demonstrates the utility of MD for making gross structural predictions based on related structures. The binding loop of the intact form is modeled to allow docking with serine proteinases, in particular thrombin, which most highly constrains the possible conformations of the binding loop.