*library_books*

## Similar protocols

## Protocol publication

[…] The central
geometric construct employed by AlphaSpace is alpha
sphere, a geometric feature derived from the Voronoi diagram of a
set of points in three-dimensional space. The Voronoi diagram is a tessellation of the space containing the
points into a set of Voronoi cells, or polyhedrons, formed from planes
that bisect adjacent points from the set. The alpha sphere centers
are defined at the vertices of this tessellation. Each alpha sphere
center will be an intersection of six bisecting planes and equidistant
to exactly four points from the set. The concept of applying Voronoi
tessellation to protein structure was first introduced by Richards
in 1974, along with the “weighted”
Voronoi tessellation, a variation in the calculation to account for
different atomic radii that was later implemented by Liang et al.
in CAST. AlphaSpace employs the “classical”
Voronoi tessellation, also used by **fpocket**, for which all atoms are treated as equivalent points. In this case,
the alpha sphere makes contact with the centers of exactly four atoms
but is otherwise empty of other atomic centers. Its radius is measured
from alpha sphere center to atom center. Alpha spheres centered outside
the protein surface mark concave surface regions and can be used to
represent potential interaction space. A illustrates how a Voronoi diagram can be
used to map the concave interaction space in a two-dimensional schematic
model of shallow pockets in a surface.With AlphaSpace, we introduce two additional alpha sphere-related
geometric features: alpha-atom and alpha-space (B,C). An alpha-atom shares a center with
its associated alpha sphere but with a reduced radius set to 1.8 Å.
An alpha-atom can be thought of as a theoretical ligand atom at a
discrete interaction point, positioned to make approximate contact
with the small region of protein surface associated with the set of
four alpha sphere contact atoms. The alpha-space is the volume of
the tetrahedron defined by the centers of the four alpha sphere contact
atoms. Every alpha-atom has an associated alpha-space, the volume
of which captures information about the relative positions of the
four contact atoms, which is related to the structure of the surface
region associated with these four atoms. The set of all alpha-spaces
for a set of points is equivalent to its Delaunay triangulation, the
dual graph of the Voronoi diagram.AlphaSpace fragment-centric
topographical mapping (FCTM) is performed
in two stages: pocket identification and pocket evaluation, as shown
in . [...] Selected pockets from the
first stage are quantitatively characterized in Stage 2 of AlphaSpace
FCTM. The analysis includes Pocket ranking, Pocket-fragment complementarity, Pocket matching, and Pocket communities, as illustrated in . Pocket evaluation
is facilitated by the alpha-atom and alpha-space features and provides
a high-resolution map of underutilized and targetable pocket space
at a PPI interface.We use alpha-space as a geometric feature
related to the size and shape of a localized region of protein surface.
The size of an individual alpha-space reflects the surface area and
curvature of the small surface region associated with the set of four
alpha sphere “contact” atoms (). While the set of alpha spheres in an alpha-cluster
will overlap, the corresponding set of alpha-spaces will fit face-to-face
to form a contiguous volume. This allows for the sum over all alpha-spaces
within a pocket to serve as a single metric that approximates the
surface area and curvature of the complete pocket. Figure S5 illustrates the geometric relationship between the
alpha-atom and the alpha-space in the context of an alpha-cluster
(the Trp92 pocket from Mdm2/p53).The alpha-atom construct can
be used to calculate the alpha-cluster
contact surface area (ACSA) for each individual pocket. When alpha
spheres are clustered to define a pocket, the corresponding alpha-atoms
form an overlapping alpha-cluster, the outline of which represents
the approximate shape and size of that pocket’s complementary
pseudofragment (). To calculate the atomistic ACSAs for an individual pocket, we
use **Naccess** to calculate the atomistic
accessible surface areas for the protein structure alone and then
for the same protein in complex with that pocket’s single alpha-cluster.
Subtracting the atomistic values associated with the alpha-cluster
complex from the corresponding atomistic values associated with the
protein alone will yield non-zero (and positive) values only for the
set of atoms in direct contact with the alpha-cluster. These differences
are taken as the atomistic surface areas associated with that individual
pocket. The sum of these atomistic values provides the total ACSA
for that pocket. […]

## Pipeline specifications

Software tools | fpocket, Naccess |
---|---|

Applications | Protein structure analysis, Protein physicochemical analysis |