Multi-physics models and robotics algorithms for protein computer-aided design – ProtiCAD

The methodological breakthrough expected from this interdisciplinary project builds on the combination of cutting-edge techniques developed in computational structural biology with efficient algorithms originating from robotics for computing motions of highly-complex articulated mechanisms. The goal of this interdisciplinary approach is to overcome the current limitations of CPD techniques, in particular regarding protein backbone flexibility and ligand accessibility. Another key aspect for successful protein design that will be investigated in the project concerns the development of effective energy functions that are both accurate and yet sufficiently fast for exploring large regions of the conformational-sequence space. The computational design techniques will be integrated into a software prototype and tested for validation on benchmark systems. Feedback forms these tests will be used to improve the methods. Ultimately, these methods will be applied to the challenging problem of protein de novo design; in particular, to redesign novel minimalist protein scaffolds of biological systems of relevance for biotechnologies.

The project has been running for only 6 months. There are not significant results yet.

The aim of this fundamental research project is to yield methodological advances in computational protein design. At a mid/long term, the project could favor the development of software industry in this area. In addition, results of this project could have an indirect impact in different application domains making use of (designed) proteins: biotechnology, biomolecular nanotechnology, molecular medicine and synthetic biology. Particularly, thanks to interaction with the Toulouse White Biotech center (TWB), we would expect that computational tools issued from this project could accelerate the conception of new enzymes used in white biotechnologies. Thus, the project could help promoting the development of an innovative bio-economy, respectful of the environment.

The project has been running for only 6 months. Some publications have been already submitted. There are not patents issued from the project yet.

Proteins are essential parts in living organisms. They participate in most of the cellular processes such as gene expression, signal transmission, catalysis of chemical reactions, … Due to their large range of possible functions, the study of proteins interests other fields in addition to biology. Proteins are pharmaceutical targets and drugs, their catalytic properties are widely used in biotechnology, and they are used as components of nano-devises in the rising field of bionanotechnology. Although the properties of natural proteins can be directly exploited, new, designed proteins, with novel functions or improved activities, are of major interest in all these application areas.

Protein design may involve the remodeling of a known protein scaffold in order to modify the protein function/activity, or, in the most general case, the complete (de novo) design of new protein structures to fulfill a particular function. The problem is extremely challenging since the number of possible combinations of amino acids to be tested is astronomically large. Experimentally testing all the possible sequences is practically impossible. Therefore, computational protein design methods have been developed for over a decade. In addition to the intrinsic combinatorial complexity of the protein design problem, computational methods have to face the natural flexibility of proteins (i.e. proteins are flexible molecules that fluctuate between nearly isoenergetic states). Indeed, the protein design problem is even more challenging if dynamical aspects (e.g. allosteric shifts, loop motions, ...) are considered in addition to static aspects (e.g. positional arrangement of catalytic residues for enzyme activity).

Due to all these difficulties, and despite great advances in recent years, computational protein design remains a largely open problem. In particular, improvements in models and algorithms are essential to better explore the protein sequence combinatorial space while taking into account protein flexibility. Besides, accurate and computationally efficient energy functions, able to better account for interactions with solvent and entropy change, are necessary.

The goal of this project is to yield advances in a general methodology for protein design, and to develop suitable computational design tools that will lead the development of new proteins for applications in biotechnology, biomolecular nanotechnology, molecular medicine and synthetic biology. The methodological breakthrough expected from this interdisciplinary project builds on the combination of cutting-edge methods in computational biology with efficient algorithms originating from robotics.

Among all the possible applications of the methods developed in this project, special attention will be given to enzyme design for applications in biotechnology such as the production of high-valued molecules, the development of eco-friendly bioprocesses and the valorization of renewable carbon resources. Such applications are of high interest to the pre-industrial demonstrator Toulouse White Biotech (TWB), supporter of our project, and to the Competitive Cluster AgriMip.

The achievement of the project relies on the complementary expertise of four partners: LAAS-CNRS for robotics and computer science, BIOS-Polytechnique and LISBP-INSA for computational biology & protein engineering, and Kineo CAM, a company specialized in software development for computer-aided design and manufacturing.