Advanced Protein Modeling

Overview

The recognition of homology between protein sequences and known structures provides invaluable information towards understanding the biological behavior and biochemical function of uncharacterized sequences, and enables prediction of three-dimensional structures through comparative modeling. The Advanced Protein Modeling package in SYBYL enables the user to perform both homolog finding and comparative modeling through a streamlined interface.

Using the FUGUE™ technology, structural homologs of a target sequence can be identified by sequence-structure comparison using a database of detailed structural profiles of all known protein families. A protein family's structural profile comprises an environment-specific substitution table that takes into account secondary structure, solvent accessibility and hydrogen-bonding interactions, and structure-dependent gap penalties. These tables are derived from the structural alignments of experimentally determined protein structures in HOMSTRAD™, a database containing thousands of 3D protein structures clustered into related families. The key elements of FUGUE are environment-specific substitution tables, structure-dependent gap penalties, automated alignment method selection, and HOMSTRAD.

Using the ORCHESTRAR™ technology, comparative models can be built from a target sequence using single or multiple structural homologs found by FUGUE or provided by the user. In this process, sequence alignment is paramount to the success of model building. The ORCHESTRAR interface in SYBYL allows the user to align sequences using homology, local structural environment, manual editing, or import from external tools. Homologs are structurally aligned based using homology and local structural environment, and then structurally conserved regions are identified using backbone curvature and torsion in addition to C-alpha rmsd and homology. Loops (structurally variable regions) are then modeled by knowledge-based or ab initio approaches, and sidechains are added by enumerating rotamer combinations constrained by borrowing as much information from the parent homologs as possible. Finally, a range of analysis tools are available to highlight potential problems with the structure and allow the user to iterate through the process and refine initial models.

Advanced Protein Modeling Brochure (635k)

Comparison of homology model of human factor Xa (Stuart-Prower factor, white) to the crystal structure (2BOK.pdb, orange), created using Advanced Protein Modeling. Sequence identities between the target and the five homologs used in modeling ranged between 40%-80%. The RMSD between the backbones of the model and the crystal structure is 1.5 A.

Key Benefits

• Identify and validate an uncharacterized target sequence based on its association with known protein families.
• Generate knowledge useful in selecting compounds for screening or virtual screening experiments.
• Derive accurate sequence alignments and produce 3D models of the target and/or as the basis for structure-based design and virtual screening studies.
• Interactively visualize multiple sequence alignments and corresponding 3D protein structures
• Streamlined workflow to guide the user through the complex comparative modeling process
• Align structures based on local structural environment as well as homology
• Find structurally conserved regions based on multiple homolog templates using curvature and torsion
• Use knowledge-based methods in conjunction with ab initio methods to find the best loops and sidechain conformations
• Focus on each key step to improve model success or click-through each step with default settings to quickly produce a rough model