SWISS-MODEL is a structural bioinformatics web-server dedicated to homology modeling of 3D protein structures. Homology modeling is currently the most accurate method to generate reliable three-dimensional protein structure models and is routinely used in many practical applications. Homology (or comparative) modelling methods make use of experimental protein structures ("templates") to build models for evolutionary related proteins ("targets").
Today, SWISS-MODEL consists of three tightly integrated components:
(1) The SWISS-MODEL pipeline – a suite of software tools and databases for automated protein structure modelling,
(2) The SWISS-MODEL Workspace – a web-based graphical user workbench,
(3) The SWISS-MODEL Repository – a continuously updated database of homology models for a set of model organism proteomes of high biomedical interest.
SWISS-MODEL pipeline comprises the four main steps that are involved in building a homology model of a given protein structure:
The SWISS-MODEL server template library ExPDB is extracted from the PDB. In order to allow a stable and automated workflow of the server, the PDB coordinate files are split into individual protein chains and unreliable entries. Additional information useful for template selection is gathered and added to the file header, e.g. probable quaternary structure, quality indicators like empirical force field energy or ANOLEA mean force potential scores.
Up to five template structures per batch are superposed using an iterative least squares algorithm. A structural alignment is generated after removing incompatible templates, i.e. omitting structures with high Cα root mean square deviations to the first template. A local pair-wise alignment of the target sequence to the main template structures is calculated, followed by a heuristic step to improve the alignment for modeling purposes. The placement of insertions and deletions is optimized considering the template structure context.
To generate the core of the model, the backbone atom positions of the template structure are averaged. The templates are thereby weighted by their sequence similarity to the target sequence, while significantly deviating atom positions are excluded. The template coordinates cannot be used to model regions of insertions or deletions in the target-template alignment. To generate those parts, an ensemble of fragments compatible with the neighboring stems is constructed using constraint space programming (CSP). The best loop is selected using a scoring scheme, which accounts for force field energy, steric hindrance and favorable interactions like hydrogen bond formation. If no suitable loop can be identified, the flanking residues are included to the rebuilt fragment to allow for more flexibility.
Side chain modeling
The reconstruction of the model side chains is based on the weighted positions of corresponding residues in the template structures. Starting with conserved residues, the model side chains are built by iso-sterically replacing template structure side chains. Possible side chain conformations are selected from a backbone dependent rotamer library, which has been constructed carefully taking into account the quality of the source structures. A scoring function assessing favorable interactions (hydrogen bonds, disulfide bridges) and unfavorably close contacts is applied to select the most likely conformation.
Deviations in the protein structure geometry, which have been introduced by the modeling algorithm when joining rigid fragments are regularized in the last modeling step by steepest descent energy minimization using the GROMOS96 force field. Empirical force fields are useful to detect parts of the model with conformational errors. In our own experience and the work of others, energy minimization or molecular dynamics methods are in general not able to improve the accuracy of the models, and are used in SWISS-MODEL only to regularize the structure.
Many tools are provided to allow the SWISS-MODEL user to evaluate the reliability of the model: similar to B-factors in crystal structures, the corresponding column in SWISS-MODEL result files consists of a C-score, which gives an estimate of the variability of the template structures at this position. Parts of the model where no template information could be used for model building (insertions or deletions) are assigned a C-score of 99. Optionally, WhatCheck reports and evaluation by the atomic mean force potential ANOLEA are provided by SWISS-MODEL to assess the quality of the model.
The program DeepView (Swiss-PdbViewer) can be used to revise the resulting SWISS-MODEL projects from ‘first approach’ mode submissions.