Aashish_PhD_Thesis_edited.pdf (2.52 MB)

Machine Learning Approaches Towards Protein Structure and Function Prediction

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posted on 04.08.2021, 14:33 by Aashish JainAashish Jain

Proteins are drivers of almost all biological processes in the cell. The functions of a protein are dependent on their three-dimensional structure and elucidating the structure and function of proteins is key to understanding how a biological system operates. In this research, we developed computational methods using machine learning techniques to predicts the structure and function of proteins. Protein 3D structure prediction has advanced significantly in recent years, largely due to deep learning approaches that predict inter-residue contacts and, more recently, distances using multiple sequence alignments (MSAs). The performance of these models depends on the number of similar protein sequences to the query protein, wherein some cases similar sequences are few but dissimilar sequences with local similarities are more and can be helpful. We have developed a novel deep learning-based approach AttentiveDist which further improves over the previous state of art. We added an attention mechanism where dis-similar sequences are also used (increasing number of sequences) and the model itself determines which information from such sequences it should attend to. We showed that the improvement of distance predictions was successfully transferred to achieve better protein tertiary structure modeling. We also show that structure prediction from a predicted distance map can be further enhanced by using predicted inter-residue sidechain center distances and main-chain hydrogen-bonds. Protein function prediction is another avenue we explored where we want to predict the function that a protein will perform. The crux of the approach is to predict the function of protein based on the function of similar sequences. Here, we developed a method where we use dissimilar sequences to extract additional information and improve performance over the previous approaches. We used phylogenetic analysis to determine if a dissimilar sequence can be close to the query sequence and thus can provide functional information. Our method was ranked highly in worldwide protein function prediction competition CAFA3 (2016-2019). Further, we expanded the method with a neural network to predict protein toxicity that can be used as a safety check for human-designed protein sequences.


Degree Type

Doctor of Philosophy


Computer Science

Campus location

West Lafayette

Advisor/Supervisor/Committee Chair

Daisuke Kihara

Additional Committee Member 2

Alex Pothen

Additional Committee Member 3

Jean Honorio

Additional Committee Member 4

Xavier Tricoche