6 research outputs found
Local topological modification of hexahedral meshes. Part I: A set of dual-based operations
For hexahedral meshes, it is difficult to make topological modifications which preserve conformal property
and which are local to the modified elements. This is most easily understood in how changes affect the dual
surfaces (sheets) and lines (chords), which have non-local extent in hexahedral meshes. A set of three operations
is proposed which represent distinct local changes to the hex mesh and its dual. These operations are shown to compose
the larger set of (lipping) operations described by Bern et. al. The relation between these dual-based operations and
the insertion of a Boy surface in the dual, described by Bern, is also discussed
Active Site Mapping of an Aspartic Protease by Multiple Fragment Crystal Structures: Versatile Warheads To Address a Catalytic Dyad
Crystallography is frequently used
as follow-up method to validate
hits identified by biophysical screening cascades. The capacity of
crystallography to directly screen fragment libraries is often underestimated,
due to its supposed low-throughput and need for high-quality crystals.
We applied crystallographic fragment screening to map the protein-binding
site of the aspartic protease endothiapepsin by individual soaking
experiments. Here, we report on 41 fragments binding to the catalytic
dyad and adjacent specificity pockets. The analysis identifies already
known warheads but also reveals hydrazide, pyrazole, or carboxylic
acid fragments as novel functional groups binding to the dyad. A remarkable
swapping of the S1 and S1′ pocket between structurally related
fragments is explained by either steric demand, required displacement
of a well-bound water molecule, or changes of trigonal-planar to tetrahedral
geometry of an oxygen functional group in a side chain. Some warheads
simultaneously occupying both S1 and S1′ are promising starting
points for fragment-growing strategies
Active Site Mapping of an Aspartic Protease by Multiple Fragment Crystal Structures: Versatile Warheads To Address a Catalytic Dyad
Crystallography is frequently used
as follow-up method to validate
hits identified by biophysical screening cascades. The capacity of
crystallography to directly screen fragment libraries is often underestimated,
due to its supposed low-throughput and need for high-quality crystals.
We applied crystallographic fragment screening to map the protein-binding
site of the aspartic protease endothiapepsin by individual soaking
experiments. Here, we report on 41 fragments binding to the catalytic
dyad and adjacent specificity pockets. The analysis identifies already
known warheads but also reveals hydrazide, pyrazole, or carboxylic
acid fragments as novel functional groups binding to the dyad. A remarkable
swapping of the S1 and S1′ pocket between structurally related
fragments is explained by either steric demand, required displacement
of a well-bound water molecule, or changes of trigonal-planar to tetrahedral
geometry of an oxygen functional group in a side chain. Some warheads
simultaneously occupying both S1 and S1′ are promising starting
points for fragment-growing strategies