some movies added to demonstrate what you can do with FlexTree/pyDock, see Movie section
Cone Motion -- local perturbation of domain implemented
Rotamer library (by Dunbrack, et.al) added to FlexTree to
describe the sidechain
What is
FlexTree?
FlexTree (FT) is a package.writen in Python.
FT is
designed to representation of conformational sub-spaces of proteins,
especially the ones with large domain motion and / or induced fit
effect.
Two major issues rise in the study of protein
flexiblity . What and How. What : What
are the domains in the flexible protein? In this study, the
domain refers to the rigid bodies whose internal coordinations don't
change (much) during the simulation. Example incudes the 'flap' domain
in HIV protease and "EFG1/2" domains in Tissue Factor protein. How :
After the protein being partitioned into domains, how can we describe
the motion of each domain? Do they translate in 3D space? rotate about
an axis? shear?
These two topics have been studied in the last
decade or so. Several software packages are available to partition the
protein into rigid domains. Some are capable of finding out hinge
axises.
FlexTree doesn't derive flexibiliy information from
structures. The answers to "What" and "How" are taken from the widely
available software and employed to encode the conformational
subspace. Information about protein flexibility in stored in
XML format ( example )
FlexTree, as the name suggests, is built in a tree
structure. All the nodes in the tree are FlexTree Nodes (FTNode). Every
level of the tree represents a different resolution, or approximation
of the protein. For example, The HIV protease can be taken as a rigid
protein, as shown in the root FTNode of FlexTree. The protease, as a
dimer, has two chains. The level first level of FlexTree has two
FTNodes, Chain A and B. At this level, the two chains can move ralative
to each other as a rigid body. Each of the chain can be further divided
into flap and core, with more detailed description of the protein. The
Flap / Core can still be devided into residues and then atoms for more
explicit conformations, if necessory. An motion object is associated
with every FTNode in the tree structure. Now the FlexTree
supports hinge motion, translation, screwing, local perturbation, etc.
Potential applications include: (shameless
stolen from AutoDock page)
structure-based drug design
protein-ligand docking
protein-protein docking
lead optimization
virtual screening (HTS)
combinatorial library design
protein-protein docking
chemical mechanism studies
Application in Docking studies
The conformational space encoded by a FlexTree can be
searched using generic algorithm (GA) for a docking study.
Pair-wise scoring function (instead of grid map) is used in this approach.
The parameters that describe the motions in FlexTree is taken as
'gene' for GA searching
Global Searching Methond
Generic Algorithm from
SciPy community
Scoring function
AutoDock 3.05 force field.
(Python and C++ version) (thanks to Lindy and Ruth ! )
A python script pyDock (temporary name) is available
here. Docking configuration here.
Hinge motion of Adenylate kinase (1.5MB)
4AKE and 2ECK are partitioned into moving domain and fixed domain by
DynDom
The best a hinge motion can do to superimpose a moving domain from open to close is RMSD =1.729A (2.2MB)
with random local perturbation, the hinge motion can bring moving domain to RMSD=1.292A (2.8MB)
with random local perturbation, the hinge motion can bring moving domain to RMSD=1.270A (2.6MB)
with random local perturbation, the hinge motion can bring moving domain to RMSD=1.303A (2.9MB)
Re-docking of XK263 to HIV protease
(PDB ID: 1HVR)
the "flap" and "core" domains are colored differently. motion
parameters derived from open conformation (3hvp) and closed
conformation (4hvp)
Better resolution, different background movies can be found
here (21.8MB),
here (41.6MB)and
here (34.9MB)
see how SB203SB238 was (re-)docked back to
1HBV, with 7 residues from receptor flexible (51.3MB, 4min22sec)
magenta: SB203SB238 ligand in crystal structure.
yellow: the same ligand in docking test
Contact
The FlexTree development team includes Yong Zhao and Daniel Stoffler, under the direction of Dr. Michel Sanner.
Any input / feedback is welcome ! Please email to Dr.
Zhao
yongzhao__at__scripps.edu ( replace
the __at__ with '@') Dr.
Stoffler
Daniel.Stoffler__at__unibas.ch
or to Dr. Sanner
sanner
_at_ scripps.edu
Mailing Address
The Scripps Research Institute,
Dept. Molecular Biology, TPC26,
10550 North Torrey Pines Road,
La Jolla, CA 92037-1000, USA.
Fax: (858) 784-2860
