A m ajor com ponent of the docking algorithm to be presented
w ill be the use o f a soft potential to search for areas o f steric
co m p lem en tarity betw een the m olecular surfaces o f ho st and guest
p ro tein s. T h is search will only be e ffe c tiv e if the lo ck -a n d -k ey
binding m odel is largely correct. The level o f c o m p lem en tarity at
p ro te in /p ro te in in te rfac es can be ju d g e d by e x am in in g the three
know n antibody/lysozym e com plexes (Table 2.1).
T he n a tu r e o f the a n tib o d y /a n tig e n in te r f a c e has been
d escrib ed (M ian, et a l , 1991; Padlan, 1990; W illiam, et al., 1990). In o rd er to test fu rth er the steric co m p lem en tarity in this region a
v o lu m e c a l c u l a t i o n w as c a r r ie d o u t on e a c h o f th e th re e
antibody/lysozym e complexes. The m ethod used was that of Gellatly
& Finney (1982). A hypothetical solvent shell was placed around the
com plex. The shell com pletely surrounded the com plex but did not
seep into the antib o d y /ly so zy m e interface. The vo lu m e inside this
sh ell w as then d iv id ed betw een the atom s in the c o m p lex , in
proportion to their van der W aals radii. This involved finding nearest
n e ig h b o u rs to each atom and p la c in g a p la n e b e tw ee n th em ,
p e rp e n d icu lar to the line passing directly though the atom centres
and with distances between the plane and the atoms in proportion to
th eir van der W aals radii. M any such planes were created around
each atom until a closed polyhedron was formed. The volume of this
polyhedron was taken to be the volume occupied by the atom.
S t r u c t u r e Resolution (Â) PDB file A u t h o r
H yH E L -10 3 .0 PDB3HFM Padlan et al.
( 1 9 8 9 )
HyHEL-5 2 .5 PDB2HFL Sheriff et al.
( 1 9 8 7 )
D1.3 2 . 8 o b t a i n e d f r o m
Dr S. Phillips
Amit et al.
( 1 9 8 6 )
L y s o z y m e 2 . 0 PDB6LYZ Diamond et al.
( 1 9 7 4 )
Table 2.1
P r o te in s tr u c tu r e d a ta fo r th e th re e a n t i b o d y / ly s o z y m e
c om plexes and for the unbound form of lysozym e. The structures
have resolutions betw een 2Â and 3Â, sufficient to correctly assign
m ain -ch a in and sid e-ch ain structure. T h ree o f the stru c tu re s are
d e p o site d in the B ro o k h av en Protein D ataB an k (B e rn stein et al.,
O nce volumes have been assigned to each atom, it was possible
to find the mean volume occupied by each atom type. For each atom
type an expected volum e was calculated by averaging the volum e
re s u lts fo r several p ro tein s, n o t in c lu d in g the a n tib o d y /ly s o z y m e
com plexes. E xam ining the d ifferences betw een the volum es seen at
the interface and those seen on average allowed an estim ation of the
packing density relative to the protein core
T he results of the volume calculations are sum m arised in Table
2.2. A volum e calculation was perform ed for each atom within the
in te rfac e ( V o b s e r v e d ) * The volume calculation was also carried out on
unrelated proteins, and an average volum e occupied for each atom
ty p e, w as c alcu late d (Vexpect)- This p red ic te d v o lu m e was then
com pared to the expected volume for an atom of that type. Taking a
ratio , fo r each atom , o f calcu lated vo lu m e to e x p ec te d average
volum e gives a packing density.
V*
p a c k i n g d e n s i t y observed
rt
ex p ec t
f o r a t o m i o f t y p e t
This num ber is 1.0 for an atom that occupies the standard amount of
volume. Atom s that are too tightly packed occupy too little volume
and therefore have a packing density less then 1.0, w hereas atoms
w hich are too loosely packed have a pack in g density g reater than
1.0. The packing densities shown are averages of a group o f atoms.
T he g lo b al p ack in g d e n sity is the a v erag e o v er all atom s, the
interface packing density is the average for the interface atoms. The
standard deviation of the global packing densities is also shown. The
d ifferen c e s betw een the global and in terface pack in g den sities are
very m u ch sm aller than the standard d eviation for all structures.
C o m p lex Global Packing D e n sity I n t e r f a c e Packing Density S t a n d a r d D e v ia tio n H yH E L -10 1 . 0 1 1 . 0 0 0 .1 6 HyHEL-5 0 .9 9 1 . 0 2 0 .1 8 D1.3 1 . 0 1 1 . 0 0 0 .1 8 Table 2.2 T h e r e s u l t s o f th e v o l u m e c a l c u l a t i o n s on th e
antibody/lysozym e complexes. A global packing density, an interface
packing density and the global standard deviation of packing density
is given fo r each of the co m p lex es. The p a ck in g d e n sitie s are
m easu red rela tiv e to a set o f sixty eig h t well res o lv e d protein
s t r u c t u r e s .
This m eans that the interface region is as tightly packed as the
protein core. Thus, the interface region m ust exhibit the same degree
of steric com plem entarity as the protein core. These results are in
a g re em e n t w ith those o f C h o th ia & Jan in (1975) w ho exam ined
protein/protein interface regions and found them to be close packed.