Dataset Information

Navigating the amino acid sequence space between functional proteins using a deep learning framework.

ABSTRACT:

Motivation

Shedding light on the relationships between protein sequences and functions is a challenging task with many implications in protein evolution, diseases understanding, and protein design. The protein sequence space mapping to specific functions is however hard to comprehend due to its complexity. Generative models help to decipher complex systems thanks to their abilities to learn and recreate data specificity. Applied to proteins, they can capture the sequence patterns associated with functions and point out important relationships between sequence positions. By learning these dependencies between sequences and functions, they can ultimately be used to generate new sequences and navigate through uncharted area of molecular evolution.

Results

This study presents an Adversarial Auto-Encoder (AAE) approached, an unsupervised generative model, to generate new protein sequences. AAEs are tested on three protein families known for their multiple functions the sulfatase, the HUP and the TPP families. Clustering results on the encoded sequences from the latent space computed by AAEs display high level of homogeneity regarding the protein sequence functions. The study also reports and analyzes for the first time two sampling strategies based on latent space interpolation and latent space arithmetic to generate intermediate protein sequences sharing sequential properties of original sequences linked to known functional properties issued from different families and functions. Generated sequences by interpolation between latent space data points demonstrate the ability of the AAE to generalize and produce meaningful biological sequences from an evolutionary uncharted area of the biological sequence space. Finally, 3D structure models computed by comparative modelling using generated sequences and templates of different sub-families point out to the ability of the latent space arithmetic to successfully transfer protein sequence properties linked to function between different sub-families. All in all this study confirms the ability of deep learning frameworks to model biological complexity and bring new tools to explore amino acid sequence and functional spaces.

SUBMITTER: Bitard-Feildel T

PROVIDER: S-EPMC8459775 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BackgroundThe number of applications of deep learning algorithms in bioinformatics is increasing as they usually achieve superior performance over classical approaches, especially, when bigger training datasets are available. In deep learning applications, discrete data, e.g. words or n-grams in language, or amino acids or nucleotides in bioinformatics, are generally represented as a continuous vector through an embedding matrix. Recently, learning this embedding matrix directly from the data as part of the continuous iteration of the model to optimize the target prediction - a process called 'end-to-end learning' - has led to state-of-the-art results in many fields. Although usage of embeddings is well described in the bioinformatics literature, the potential of end-to-end learning for single amino acids, as compared to more classical manually-curated encoding strategies, has not been systematically addressed. To this end, we compared classical encoding matrices, namely one-hot, VHSE8 and BLOSUM62, to end-to-end learning of amino acid embeddings for two different prediction tasks using three widely used architectures, namely recurrent neural networks (RNN), convolutional neural networks (CNN), and the hybrid CNN-RNN.ResultsBy using different deep learning architectures, we show that end-to-end learning is on par with classical encodings for embeddings of the same dimension even when limited training data is available, and might allow for a reduction in the embedding dimension without performance loss, which is critical when deploying the models to devices with limited computational capacities. We found that the embedding dimension is a major factor in controlling the model performance. Surprisingly, we observed that deep learning models are capable of learning from random vectors of appropriate dimension.ConclusionOur study shows that end-to-end learning is a flexible and powerful method for amino acid encoding. Further, due to the flexibility of deep learning systems, amino acid encoding schemes should be benchmarked against random vectors of the same dimension to disentangle the information content provided by the encoding scheme from the distinguishability effect provided by the scheme.

Dataset Information

Navigating the amino acid sequence space between functional proteins using a deep learning framework.

Motivation

Results

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