Intro:
Integrating Ankh and other proprietary models, our Protein engineering platform (PEP) is capable of multi-parameter protein optimization of complex proteins. Here, we showcase how we have integrated several components of our platform to engineer a protein integral in many biotechnology industries to enhance multiple parameters, stability, and solubility
Blog content:
- Overview of the Project
- Hits Generation
- Lead Selection & Validation
- Outperforming the Wildtype and Commercial Alternatives
Overview of the Project:
Multi-parameter protein optimization is a complex engineering problem. It involves extensive finetuning of protein amino acids towards an optimum point in the protein function landscape. Going through a protein optimization problem, a couple of problems start to emerge.
Optimizing one function of the protein is already an extensive and expensive task. A typical protein has a couple of hundreds of amino acids with 19 different possible changes in each location. In this complex problem, you are left with a significant number of variations to try.
The standard toolkit has two options:
- Random mutagenesis: which is typically random shots on the same goal
The approach is extensively utilized but has significant drawbacks, including the time and cost needed to generate and test each variant physically.
- Rational design: analysis of the structure to narrow down some guiding rules
The approach requires plenty of skills and a significant time commitment to analyze residues individually.
Proteinea’s Protein Engineering Platform (PEP) capitalizes on the advantages of both platforms being comprehensive and knowledge-based simultaneously. Our process involves training our AI models for a better understanding of protein sequence to structure to function relationships to achieve multiparameter protein optimization in significantly less time and less cost.
From generating meaningful hits to lead selection and validation, we can speed up the process significantly while having a higher probability of success.
Hits Generation:
Ankh - Meaningful Protein Representation: To model the language of life, we need a meaningful representation encompassing its structural and functional information. We used our top-performing state-of-art protein language model Ankh to represent our target.
Hidden Gems Database – Exclusive Access to Proteins and their Meaning: To build our growth factor training dataset, we leveraged Hidden Gems, our massive database with exclusive access to proteins, holistic representations, and annotations.
Gem Mining – Conquering Sparse & Novel Targets: To expand our training dataset, we utilized Gem Mining, our original search algorithm landing hits with fundamental structural and functional similarity with often low sequence similarity!
AnkhGen – In Silico Directed Evolution: To generate top-performing hits, We employed our patented approach that expands our protein goldmines from size n to size n2 to navigate hundreds of thousands of possible mutations for function-guided generation.
Lead Selection & Validation:
To deliver high-confidence variants for experimental validation, We exploited our holistic filtration engine to look for leads via a multi-layered and multi-path sequence and structural analysis. We were able to filter through hundreds of thousands of variants for the top performing leads based on the desired parameters.
For experimental testing we integrated our cloud and external labs to reinforce our computational promotion of leads outperforming top commercially available variants. Our rapid high-throughput experimental validation through our Conan PI screening platform is essential to enhancing our computational performance and empowering further iterations. We input our smart experimental feedback through our computational models to achieve even better results in subsequent
Outperforming the Wildtype and Commercial Alternatives:
Focusing on the protein thermal stability, here we show that thermal stability was enhanced itrativly over two iterations with a significant improvement in protein’s thermal stability. Additionally, the protein yield increased to over 4X (not shown) while increase or maintaining the biological functionality of the protein.
Iterative cycles of engineering takes the exceptional results into new hights.
Let’s explore how we can make your exceptional protein better
Contact us at hello@proteinea.com for more information on commercial partnerships
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