CCBuilder 2.0: Powerful and accessible coiled-coil modeling

Abstract

The increased availability of user-friendly and accessible computational tools for biomolecular modeling would expand the reach and application of biomolecular engineering and design. For protein modeling, one key challenge is to reduce the complexities of 3D protein folds to sets of parametric equations that nonetheless capture the salient features of these structures accurately. At present, this is possible for a subset of proteins, namely, repeat proteins. The α-helical coiled coil provides one such example, which represents ≈ 3-5% of all known protein-encoding regions of DNA. Coiled coils are bundles of α helices that can be described by a small set of structural parameters. Here we describe how this parametric description can be implemented in an easy-to-use web application, called CCBuilder 2.0, for modeling and optimizing both α-helical coiled coils and polyproline-based collagen triple helices. This has many applications from providing models to aid molecular replacement for X-ray crystallography, in silico model building and engineering of natural and designed protein assemblies, and through to the creation of completely de novo "dark matter" protein structures. CCBuilder 2.0 is available as a web-based application, the code for which is open-source and can be downloaded freely. http://coiledcoils.chm.bris.ac.uk/ccbuilder2.

Lay summary: We have created CCBuilder 2.0, an easy to use web-based application that can model structures for a whole class of proteins, the α-helical coiled coil, which is estimated to account for 3-5% of all proteins in nature. CCBuilder 2.0 will be of use to a large number of protein scientists engaged in fundamental studies, such as protein structure determination, through to more-applied research including designing and engineering novel proteins that have potential applications in biotechnology.

Keywords: coiled coil; collagen; computational design; parametric design; protein design; structural bioinformatics; structural modeling; synthetic biology; web app.

Figure 1

Structure of α‐helical coiled coils. (A) Helical‐wheel diagrams showing the projection of residues in the heptad repeat. (B) Helices in a coiled coil pack closely together, forming knobs‐into‐holes interactions. (C) Coiled coils can be described using three geometric parameters: interface angle (°), radius (Å), and pitch (Å).

Figure 2

Architecture of the CCBuilder 2.0 web application. The client side (Elm, JavaScript, HTML, and CSS) is used for submitting parameters and displaying models/metrics. The web backend (Flask, MongoDB, uWSGI, and NGINX) serves the application web pages and also provides an RESTful API to the modeling engine (implemented using ISAMBARD).46

Figure 3

The CCBuilder 2.0 Interface. Panels can be hidden to give a full view of the model in the molecular viewer.

Figure 4

CCBuilder 2.0 can model a diverse range of coiled coils and collagens. Top row: dimer, trimer, tetramer, pentamer, hexamer, and heptamer, which are all homotypic. Bottom row: A4/B4 heterodimer, A3/B4 heterodimer, antiparallel homodimer, slipped heptamer, and homotrimeric and heterotrimeric collagens.