The structure assessment web server: for proteins, complexes and more.

The 'structure assessment' web server is a one-stop shop for interactive evaluation and benchmarking of structural models of macromolecular complexes including proteins and nucleic acids. A user-friendly web dashboard links sequence with structure information and results from a variety of state-of-the-art tools, which facilitates the visual exploration and evaluation of structure models. The dashboard integrates stereochemistry information, secondary structure information, global and local model quality assessment of the tertiary structure of comparative protein models, as well as prediction of membrane location. In addition, a benchmarking mode is available where a model can be compared to a reference structure, providing easy access to scores that have been used in recent CASP experiments and CAMEO. The structure assessment web server is available at https://swissmodel.expasy.org/assess.

ModelCIF: An Extension of PDBx/mmCIF Data Representation for Computed Structure Models.

ModelCIF (github.com/ihmwg/ModelCIF) is a data information framework developed for and by computational structural biologists to enable delivery of Findable, Accessible, Interoperable, and Reusable (FAIR) data to users worldwide. ModelCIF describes the specific set of attributes and metadata associated with macromolecular structures modeled by solely computational methods and provides an extensible data representation for deposition, archiving, and public dissemination of predicted three-dimensional (3D) models of macromolecules. It is an extension of the Protein Data Bank Exchange / macromolecular Crystallographic Information Framework (PDBx/mmCIF), which is the global data standard for representing experimentally-determined 3D structures of macromolecules and associated metadata. The PDBx/mmCIF framework and its extensions (e.g., ModelCIF) are managed by the Worldwide Protein Data Bank partnership (wwPDB, wwpdb.org) in collaboration with relevant community stakeholders such as the wwPDB ModelCIF Working Group (wwpdb.org/task/modelcif). This semantically rich and extensible data framework for representing computed structure models (CSMs) accelerates the pace of scientific discovery. Herein, we describe the architecture, contents, and governance of ModelCIF, and tools and processes for maintaining and extending the data standard. Community tools and software libraries that support ModelCIF are also described.

3D-Beacons: decreasing the gap between protein sequences and structures through a federated network of protein structure data resources.

While scientists can often infer the biological function of proteins from their 3-dimensional quaternary structures, the gap between the number of known protein sequences and their experimentally determined structures keeps increasing. A potential solution to this problem is presented by ever more sophisticated computational protein modeling approaches. While often powerful on their own, most methods have strengths and weaknesses. Therefore, it benefits researchers to examine models from various model providers and perform comparative analysis to identify what models can best address their specific use cases. To make data from a large array of model providers more easily accessible to the broader scientific community, we established 3D-Beacons, a collaborative initiative to create a federated network with unified data access mechanisms. The 3D-Beacons Network allows researchers to collate coordinate files and metadata for experimentally determined and theoretical protein models from state-of-the-art and specialist model providers and also from the Protein Data Bank.

ProMod3-A versatile homology modelling toolbox.

Computational methods for protein structure modelling are routinely used to complement experimental structure determination, thus they help to address a broad spectrum of scientific questions in biomedical research. The most accurate methods today are based on homology modelling, i.e. detecting a homologue to the desired target sequence that can be used as a template for modelling. Here we present a versatile open source homology modelling toolbox as foundation for flexible and computationally efficient modelling workflows. ProMod3 is a fully scriptable software platform that can perform all steps required to generate a protein model by homology. Its modular design aims at fast prototyping of novel algorithms and implementing flexible modelling pipelines. Common modelling tasks, such as loop modelling, sidechain modelling or generating a full protein model by homology, are provided as production ready pipelines, forming the starting point for own developments and enhancements. ProMod3 is the central software component of the widely used SWISS-MODEL web-server.

Modeling of Protein Tertiary and Quaternary Structures Based on Evolutionary Information.

Proteins are subject to evolutionary forces that shape their three-dimensional structure to meet specific functional demands. The knowledge of the structure of a protein is therefore instrumental to gain information about the molecular basis of its function. However, experimental structure determination is inherently time consuming and expensive, making it impossible to follow the explosion of sequence data deriving from genome-scale projects. As a consequence, computational structural modeling techniques have received much attention and established themselves as a valuable complement to experimental structural biology efforts. Among these, comparative modeling remains the method of choice to model the three-dimensional structure of a protein when homology to a protein of known structure can be detected.The general strategy consists of using experimentally determined structures of proteins as templates for the generation of three-dimensional models of related family members (targets) of which the structure is unknown. This chapter provides a description of the individual steps needed to obtain a comparative model using SWISS-MODEL, one of the most widely used automated servers for protein structure homology modeling.

SWISS-MODEL: homology modelling of protein structures and complexes.

Homology modelling has matured into an important technique in structural biology, significantly contributing to narrowing the gap between known protein sequences and experimentally determined structures. Fully automated workflows and servers simplify and streamline the homology modelling process, also allowing users without a specific computational expertise to generate reliable protein models and have easy access to modelling results, their visualization and interpretation. Here, we present an update to the SWISS-MODEL server, which pioneered the field of automated modelling 25 years ago and been continuously further developed. Recently, its functionality has been extended to the modelling of homo- and heteromeric complexes. Starting from the amino acid sequences of the interacting proteins, both the stoichiometry and the overall structure of the complex are inferred by homology modelling. Other major improvements include the implementation of a new modelling engine, ProMod3 and the introduction a new local model quality estimation method, QMEANDisCo. SWISS-MODEL is freely available at https://swissmodel.expasy.org.

The SWISS-MODEL Repository-new features and functionality.

SWISS-MODEL Repository (SMR) is a database of annotated 3D protein structure models generated by the automated SWISS-MODEL homology modeling pipeline. It currently holds >400 000 high quality models covering almost 20% of Swiss-Prot/UniProtKB entries. In this manuscript, we provide an update of features and functionalities which have been implemented recently. We address improvements in target coverage, model quality estimates, functional annotations and improved in-page visualization. We also introduce a new update concept which includes regular updates of an expanded set of core organism models and UniProtKB-based targets, complemented by user-driven on-demand update of individual models. With the new release of the modeling pipeline, SMR has implemented a REST-API and adopted an open licencing model for accessing model coordinates, thus enabling bulk download for groups of targets fostering re-use of models in other contexts. SMR can be accessed at https://swissmodel.expasy.org/repository.

SWISS-MODEL: modelling protein tertiary and quaternary structure using evolutionary information.

Protein structure homology modelling has become a routine technique to generate 3D models for proteins when experimental structures are not available. Fully automated servers such as SWISS-MODEL with user-friendly web interfaces generate reliable models without the need for complex software packages or downloading large databases. Here, we describe the latest version of the SWISS-MODEL expert system for protein structure modelling. The SWISS-MODEL template library provides annotation of quaternary structure and essential ligands and co-factors to allow for building of complete structural models, including their oligomeric structure. The improved SWISS-MODEL pipeline makes extensive use of model quality estimation for selection of the most suitable templates and provides estimates of the expected accuracy of the resulting models. The accuracy of the models generated by SWISS-MODEL is continuously evaluated by the CAMEO system. The new web site allows users to interactively search for templates, cluster them by sequence similarity, structurally compare alternative templates and select the ones to be used for model building. In cases where multiple alternative template structures are available for a protein of interest, a user-guided template selection step allows building models in different functional states. SWISS-MODEL is available at http://swissmodel.expasy.org/.

Fast alignment and comparison of RNA structures.

MOTIVATION: To recognize remote relationships between RNA molecules, one must be able to align structures without regard to sequence similarity. We have implemented a method, which is swift [O(n(2))], sensitive and tolerant of large gaps and insertions. Molecules are broken into overlapping fragments, which are characterized by their memberships in a probabilistic classification based on local geometry and H-bonding descriptors. This leads to a probabilistic similarity measure that is used in a conventional dynamic programming method. RESULTS: Examples are given of database searching, the detection of structural similarities, which would not be found using sequence based methods, and comparisons with a previously published approach. AVAILABILITY AND IMPLEMENTATION: Source code (C and perl) and binaries for linux are freely available at www.zbh.uni-hamburg.de/fries.

Dynamics in Sequence Space for RNA Secondary Structure Design.

We have implemented a method for the design of RNA sequences that should fold to arbitrary secondary structures. A popular energy model allows one to take the derivative with respect to composition, which can then be interpreted as a force and used for Newtonian dynamics in sequence space. Combined with a negative design term, one can rapidly sample sequences which are compatible with a desired secondary structure via simulated annealing. Results for 360 structures were compared with those from another nucleic acid design program using measures such as the probability of the target structure and an ensemble-weighted distance to the target structure.