STRUCTURAL BIOLOGY: MACROMOLECULAR MODELING

Biopolymer
PREDICT, BUILD, AND VISUALIZE MACROMOLECULAR 3D STRUCTURE

Biopolymer provides the tools needed for building and manipulating peptide, protein, DNA/RNA, and carbohydrate structures.
The adaptable utilities make it possible to create models that compare favorably to those obtained from experimental data.1
Biopolymer is fully integrated with SYBYL® for structure prediction, model construction, structure refinement, and visualization
and analysis. FlexiDock within Biopolymer docks ligands into receptor binding sites, while allowing conformational flexibility
in both the receptor and the ligand.

Common sequence and structure file formats The Needleman-Wunsch 2 algorithm is

Applications
Create models of peptides, proteins,
RNA, DNA, and polysaccharides
Virtual mutagenesis experiments
Pattern searching of the Protein
Data Bank
Refine structures derived from
crystallography, NMR, or modeling
Create graphical displays that reveal
structure-activity relationships
Identify receptor-bound conformations
of ligands
Model Building
Biopolymer uses a residue-based approach
to simplify construction of proteins,
polysaccharides, and nucleic acids.
A sequence of residues is entered or
selected from the menu, conformational
states are set, and the resulting model
structure is instantly available for
investigation.
are recognized, allowing transfer of models
to and from NMR and X-ray crystallographic
packages to facilitate structure determination
from experimental data. Structural information
contained in PDB files, such as conformational
states, active site locations, and cofactor
atoms, is preserved upon import.
Biopolymer includes tools for constructing
complete backbones from Cα coordinates
and for adding side chains automatically.
Residues can be mutated, deleted, and
inserted, and biopolymer chains can be
broken or joined. Proteins can be cyclized
through the backbone or cross-linked via
disulfide bridges.
When the three-dimensional structure of a
protein is unknown, Biopolymer offers
sequence alignment tools to investigate
whether two or more sequences are related,
either structurally or functionally.
provided for automatically aligning
sequences, and is more discriminating than
the local alignment techniques employed by
BLAST and FASTA.
Biopolymer works with ComposerTM and
GeneFold® (both licensed separately) to
generate starting models for subsequent
refinement. Sequence alignments generated
by Biopolymer can be viewed and edited in
Composer. GeneFold employs sequence
threading methods to predict the function
and structure of a protein from its amino
acid sequence. Composer uses the files
created by GeneFold to construct 3D models
using knowledge-based homology modeling
methods.

Dictionaries support Biopolymer’s residue-

based approach. The large number of built-in
residues includes non-standard amino acids
and is easily augmented with custom residues
and blocking groups. A special dialog
interface simplifies creation of new residues
and entry of key information maintained
with each residue, such as definitions of
torsion angles and conformational states.
New dictionaries can be built for oligomers
The methyl glycoside of the Lewis b human blood group The X-ray structure of oxy-hemocyanin (1NOL) is missing four
such as peptidomimetics and peptoids. determinant complexed with Lectin IV of Griffonia surface loops due to thermal motion and disorder in the
simplicifolia. The protein is represented as tubes color-coded crystal. The beginning and end of each gap is shown in
by secondary structure type. The tetrasaccharides are shown the image.
as space-filled atoms.

STRUCTURAL BIOLOGY: MACROMOLECULAR MODELING
A closeup of the loop candidates for the gap at residues
526-531.
Features
Build complete protein backbone from
Cα trace
Automatic side chain construction
Import and export PDB, PIR, MSF
file formats
Model peptidomimetics and
other oligomers
Secondary structure prediction methods
Mutate, insert, or delete residues
Full control of monosaccharide linkage
position and branching
Automatically set standard torsions and
conformational states
Copy conformations from one sequence
to another
Renumber residues automatically
Build single- or double-stranded RNA or
DNA in standard helical forms
Phosphorylate residues
Charged or neutral protein capping groups
Multiple sequence alignment
Structure Refinement
Biopolymer includes both knowledge-based
and energy-based methods for refining
model structures. The protein database
within Biopolymer is a compilation of the
highest resolution structures from the
Protein Data Bank.3 This database can be
Biopolymer
PREDICT, BUILD, AND VISUALIZE MACROMOLECULAR 3D STRUCTURE
searched for patterns of residues, secondary Biopolymer and SYBYL together provide
structures, sequences, or Cα distances in accurate energy-based modeling of protein
order to refine structural models. or nucleic acid complexes as well as small
organic substrates. A selection of force
For example, if a protein loop is not resolved fields is available for geometry optimization
by experimental techniques or modeling, and molecular dynamics, whether for large
candidate loop conformations can be
obtained from the database using
Biopolymer’s loop search capabilities.
Random tweak 4 is an alternative method for
building loops that generates random phi
and psi angles for a polypeptide fragment.
The phi and psi angles are modified to satisfy
distance constraints derived from the
structural gap.
Analysis tools within the Molecular
Spreadsheet allow candidate loops to be
compared and prioritized on the basis of
sequence similarity, geometric fit, torsion
and distance measurements, and steric
interactions with the protein. Interactive
displays link spreadsheet data, graphs, and The completed protein structure, after addition and
optimization of the four missing loops. The structure is
structural models to facilitate interpretation
color-coded by crystallographic B-factor, with the modeled
of results. loops shown in red-orange.
133 Loop Suitability
Homology
Origin
BUMPS
Fit_RMS
The best loops are found at the vertex of the graph giving high sequence homology, low RMS fit, and a small number of bad vdW
contacts. Loops can be selected interactively based on spreadsheet data.

STRUCTURAL BIOLOGY: MACROMOLECULAR MODELING
biomolecular assemblies, for small
molecules, or for some combination of
these structures.
Validated force fields include Tripos,5
MMFF94,6 and AMBER.7 Special routines
make it possible to optimize strained or
poorly resolved sections of biopolymers
such as surface loops while preserving high
quality regions of the models.
Features
Validated Tripos, MMFF94, and AMBER
force fields for energy refinement
Customizable database of high-quality
protein structures for searching
Loop search and random tweak for
building protein loops
Analysis and Visualization
Biopolymer’s specialized analysis and
visualization tools make it easy to access
the information inherent in macromolecular
stuctures. Through Biopolymer’s menu,
macromolecules can be searched to locate
secondary structure elements, standard
torsions can be measured, and structures
can be aligned by homology. An RMSD fit of
specified sequences in two different
structures can be performed. When multiple
structures are available, for example from
NMR-based structure calculations, regions that
have the lowest conformational variability
can be automatically located and fit.
Simplified macromolecular display options
that highlight secondary structure elements
include tubes and ribbons. CrystalEyes® and
Stereo ViewTM hardware are supported for
stereo viewing. Z-clipping and depth cueing
make it possible to focus on regions of
interest and are easily adjusted using
SYBYL’s graphical tool box.
Additional analysis tools are available in
ProTableTM (separately licensed) for the
evaluation of protein structures. ProTable
creates Ramachandran plots, assesses
deviation of local geometries and side chain
rotameric states from standard protein
values, and determines the energetics of
each residue.
Biopolymer works seamlessly with
MOLCADTM and SiteIDTM (both licensed
separately) for assessment of surface
properties and determination of binding
sites. MOLCAD creates electron density and
Connolly solvent-accessible surfaces of
molecules onto which it maps lipophilicity,
electrostatic potential, hydrogen bonding
sites, and other properties. Cavities, surfaces
between molecules, and intramolecular
channels can also be visualized. SiteID
provides tools for identifying potential
binding sites within or at the surface of
macromolecules. Once a binding pocket is
identified, SiteID can automatically create
the files required by FlexXTM (licensed
separately) to rapidly dock databases
of ligands.
Features
Ribbon or tube displays
Cα or backbone atom displays
Color atoms by B-factor
Automatically measure standard torsions
RMSD comparison of two or
more structures
Align structures by homology
Docking
Biopolymer’s FlexiDock docks ligands into
protein binding sites in order to predict
their bound conformations. FlexiDock allows
both the ligand and the receptor binding
pocket to flex during docking so that an
induced fit between enzyme and inhibitor
can be explored.
FlexiDock is composed of two main
components – a genetic algorithm for
altering the ligand conformation, the
receptor site, and their relative fit; and an
energy evaluation function for scoring the
resulting interaction. These two components
are combined into a simple, easy-to-use
interface for rapid setup.
Biopolymer
PREDICT, BUILD, AND VISUALIZE MACROMOLECULAR 3D STRUCTURE
Amino Acid Sequence
GeneFold, Composer
Advanced Computation
ProTable, MatchMaker
MOLCAD, SiteID
UNITY
FlexX, CScore
Lead Candidates
Starting from amino acid sequence, Biopolymer and SYBYL
work with other Tripos software to speed the identification
of lead candidates. GeneFold analyzes protein sequences to
predict their function and structure, and generates files
that Composer uses to create 3D coordinates. The resulting
model can be refined by molecular dynamics using
Advanced Computation. The quality of the refined structure
is assessed by ProTable and MatchMakerTM. MOLCAD cre-
ates surface displays that support SiteID’s location of
potential binding sites within or on the protein’s surface.
Once the binding site has been identified, UNITY queries are
readily constructed for searching corporate or vendor data-
bases to uncover potential lead compounds. FlexX and
CScore together perform virtual high-throughput screening
to prioritize these compounds for synthesis or screening.
The FlexiDock scoring function is based on
the Tripos Force Field and estimates the
energy of the ligand, the receptor-binding
pocket, and the interaction between them.
The scoring function can be fine-tuned by
including or ignoring the electrostatic,
torsional, or constraint terms in the
evaluation function. Hydrogen bond donors
and acceptors on both ligand and receptor
can be designated, and the proximity of
complementary sites can be included in the
scoring function.
Features
Dock ligands into a receptor
Ligand and macromolecule flexibility
Genetic algorithm for conformational
searching
Continuous or grid-based energy
evaluation
Tailorable scoring function that allows
user-specified hydrogen bonding sites

STRUCTURAL BIOLOGY: MACROMOLECULAR MODELING
Complementary Software
Advanced Computation for exploring the
conformational properties of compounds.
Composer for constructing 3D homology
models of proteins.
CScoreTM for ranking the affinity of
ligands bound to a target with consensus
scoring.
FlexX for flexibly docking ligands into a
binding site.
FUGUETM for recognizing distant
homologues by sequence-structure
comparison.
GeneFold for identifying protein function
from sequence.
LeapFrog® for performing de novo ligand
design.
MatchMaker for building 3D models of
proteins from sequence using inverse-
folding techniques.
MOLCAD for visualizing molecular
surfaces and properties.
ORCHESTRAR TM for comparative protein
modeling.
ProTable for analyzing and assessing the
quality of protein structures.
SiteID for finding and visualizing protein
binding sites.
UNITY® for locating compounds in
databases that match a pharmacophore
or fit a receptor site
AUSTRALIA
+61 (7) 5439 9775
Biopolymer
PREDICT, BUILD, AND VISUALIZE MACROMOLECULAR 3D STRUCTURE
Hardware and Software Requirements
Biopolymer requires a separate license in
addition to a SYBYL/Base license.
Biopolymer runs on workstations operating
under IRIX® (SGI®) or Linux® (x86).
References
1. Kiyama, R.; Tamura, Y.; Watanabe, F.; Tsuzuki, H.;
Ohtani, M.; Yodo, M. “Homology Modeling Of
Gelatinase Catalytic Domains And Docking
Simulations Of Novel Sulfonamide Inhibitors.”
J. Med. Chem. 1999, 42, 1723.
2. Needleman, S.B.; Wunsch, C.D. “A General Method
Applicable To The Search For Similarities In The
Amino Acid Sequence Of Two Proteins.”
J. Mol. Biol. 1970, 48, 443.
3. Berman, H.M.; Westbrook, J.; Feng, Z.; Gilliland, G.;
Bhat, T.N.; Weissig, H.; Shindyalov, I.N.; Bourne, P.E.
“The Protein Data Bank.” Nucleic Acids Res.
2000, 28, 235. http://www.rcsb.org/pdb/
4. Fine, R.M.; Wang, H.; Shenkin, P.S.; Yarmush, D.L.;
Levinthal, C. “Predicting Antibody Hypervariable
Loop Conformations. II: Minimization And Molecular
Dynamics Studies Of MCPC603 From Many
Randomly Generated Loop Conformations Proteins.”
1986, 1, 342.
5. Clark, M.; Cramer III, R.D.; Van Opdenbosch, N.
“Validation of the General Purpose Tripos 5.2 Force
Field.” J. Comp. Chem. 1989, 10, 982.
6. i) Halgren, T. “Merck Molecular Force Field. I. Basis,
Form, Scope, Parameterization, and Performance of
MMFF94.” J. Comput. Chem. 1996, 17, 720.
ii) Halgren, T. “MMFF VI. MMFF94S Option for
Energy Minimization Studies.” J. Comp. Chem.
1999, 20, 720-729.
7. Cornell, W.D.; Cieplak, P.; Bayly, C.I.; Gould, I.R.;
Merz Jr., K.M.; Ferguson, D.M.; Spellmeyer, D.C.;
Xov, T.; Caldwell, J.W.; Kollman, P.A. “A Second
Generation Force Field for the Simulation of
Proteins, Nucleic Acids, and Organic Molecules.”
J. Am. Chem. Soc. 1995, 117, 5179.
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