The inverse Potts problem for estimating evolutionary single-site fields and pairwise couplings in homologous protein sequences from their single-site and pairwise amino acid frequencies observed in their multiple sequence alignment would be still one of useful methods in the studies of protein structure and evolution. Since the reproducibility of fields and couplings are the most important, the Boltzmann machine method is employed here, although it is computationally intensive. In order to reduce computational time required for the Boltzmann machine, parallel, persistent Markov chain Monte Carlo method is employed to estimate the single-site and pairwise marginal distributions in each learning step. Also, stochastic gradient descent methods are used to reduce computational time for each learning. Another problem is how to adjust the values of hyperparameters; there are two regularization parameters for evolutionary fields and couplings. The precision of contact residue pair prediction is often used to adjust the hyperparameters. However, it is not sensitive to these regularization parameters. Here, they are adjusted for the fields and couplings to satisfy a specific condition that is appropriate for protein conformations. This method has been applied to eight protein families.

Generative protein language models are a natural way to design new proteins with desired functions.

Generative protein language models are a natural way to design new proteins with desired functions. However, current models are either difficult to direct to produce a protein from a specific family of interest, or must be trained on a large multiple sequence alignment (MSA) from the specific family of interest, making them unable to benefit from transfer learning across families.

Generative protein language models are a natural way to design new proteins with desired functions.

Modeling the effect of sequence variation on function is a fundamental problem for understanding and designing proteins.

Protein Language Models (PLMs) such as ESM2 (Lin et al., 2023) have been shown to be capable of zero-shot prediction of critical scalar properties of proteins ("fitness", Meier et al. (2021)). In this work, we show that injecting a dropout layer at inference time between a PLM's featurizer/embedding layer and its transformer, and averaging its output akin to Monte-Carlo dropout (Gal & Ghahramani, 2016) increases zero-shot performance on a subset of the ProteinGym dataset (Notin et al., 2023). This is the case even when the model was not trained with dropouts to begin with, and does not require retraining or finetuning of the PLM. A dropout of 0.1 seems performant across all models.

Generative protein language models are a natural way to design new proteins with desired functions. However, current models are either difficult to direct to produce a protein from a specific family of interest, or must be trained on a large multiple sequence alignment (MSA) from the specific family of interest, making them unable to benefit from transfer learning across families. To address this, we propose Protein Evolutionary Transformer (PoET), an autoregressive generative model of whole protein families that learns to generate sets of related proteins as sequences-of-sequences across tens of millions of natural protein sequence clusters. PoET can be used as a retrieval-augmented language model to generate and score arbitrary modifications conditioned on any protein family of interest, and can extrapolate from short context lengths to generalize well even for small families. This is enabled by a unique Transformer layer; we model tokens sequentially within sequences while attending between sequences order invariantly, allowing PoET to scale to context lengths beyond those used during training.

Advanced automated AI techniques allow us to classify protein sequences and discern their biological families and functions. Conventional approaches for classifying these protein families often focus on extracting N-Gram features from the sequences while overlooking crucial motif information and the interplay between motifs and neighboring amino acids. Recently, convolutional neural networks have been applied to amino acid and motif data, even with a limited dataset of well-characterized proteins, resulting in improved performance. This study presents a model for classifying protein families using the fusion of 1D-CNN, BiLSTM, and an attention mechanism, which combines spatial feature extraction, long-term dependencies, and context-aware representations. The proposed model (ProFamNet) achieved superior model efficiency with 450,953 parameters and a compact size of 1.72 MB, outperforming the state-of-the-art model with 4,578,911 parameters and a size of 17.47 MB. Further, we achieved a higher F1 score (98.30% vs. 97.67%) with more instances (271,160 vs. 55,077) in fewer training epochs (25 vs. 30).

Drug-target interaction (DTI) prediction is a challenging, albeit essential task in drug repurposing. Learning on graph models have drawn special attention as they can significantly reduce drug repurposing costs and time commitment. However, many current approaches require high-demanding additional information besides DTIs that complicates their evaluation process and usability. Additionally, structural differences in the learning architecture of current models hinder their fair benchmarking. In this work, we first perform an in-depth evaluation of current DTI datasets and prediction models through a robust benchmarking process, and show that DTI prediction methods based on transductive models lack generalization and lead to inflated performance when evaluated as previously done in the literature, hence not being suited for drug repurposing approaches. We then propose a novel biologically-driven strategy for negative edge subsampling and show through in vitro validation that newly discovered interactions are indeed true. We envision this work as the underpinning for future fair benchmarking and robust model design. All generated resources and tools are publicly available as a python package.