Kewei Li

Ruochi Zhang, Haoran Wu, Yuting Xiu et al.

In recent years, the scientific community has become increasingly interested on peptides with non-canonical amino acids due to their superior stability and resistance to proteolytic degradation. These peptides present promising modifications to biological, pharmacological, and physiochemical attributes in both endogenous and engineered peptides. Notwithstanding their considerable advantages, the scientific community exhibits a conspicuous absence of an effective pre-trained model adept at distilling feature representations from such complex peptide sequences. We herein propose PepLand, a novel pre-training architecture for representation and property analysis of peptides spanning both canonical and non-canonical amino acids. In essence, PepLand leverages a comprehensive multi-view heterogeneous graph neural network tailored to unveil the subtle structural representations of peptides. Empirical validations underscore PepLand's effectiveness across an array of peptide property predictions, encompassing protein-protein interactions, permeability, solubility, and synthesizability. The rigorous evaluation confirms PepLand's unparalleled capability in capturing salient synthetic peptide features, thereby laying a robust foundation for transformative advances in peptide-centric research domains. We have made all the source code utilized in this study publicly accessible via GitHub at https://github.com/zhangruochi/pepland

Xuechen Mu, Zhenyu Huang, Kewei Li et al.

Recent advancements in feature representation and dimension reduction have highlighted their crucial role in enhancing the efficacy of predictive modeling. This work introduces TemporalPaD, a novel end-to-end deep learning framework designed for temporal pattern datasets. TemporalPaD integrates reinforcement learning (RL) with neural networks to achieve concurrent feature representation and feature reduction. The framework consists of three cooperative modules: a Policy Module, a Representation Module, and a Classification Module, structured based on the Actor-Critic (AC) framework. The Policy Module, responsible for dimensionality reduction through RL, functions as the actor, while the Representation Module for feature extraction and the Classification Module collectively serve as the critic. We comprehensively evaluate TemporalPaD using 29 UCI datasets, a well-known benchmark for validating feature reduction algorithms, through 10 independent tests and 10-fold cross-validation. Additionally, given that TemporalPaD is specifically designed for time series data, we apply it to a real-world DNA classification problem involving enhancer category and enhancer strength. The results demonstrate that TemporalPaD is an efficient and effective framework for achieving feature reduction, applicable to both structured data and sequence datasets. The source code of the proposed TemporalPaD is freely available as supplementary material to this article and at http://www.healthinformaticslab.org/supp/.

Ruochi Zhang, Haoran Wu, Chang Liu et al.

Recent advances in protein language models have catalyzed significant progress in peptide sequence representation. Despite extensive exploration in this field, pre-trained models tailored for peptide-specific needs remain largely unaddressed due to the difficulty in capturing the complex and sometimes unstable structures of peptides. This study introduces a novel multi-view contrastive learning framework PepHarmony for the sequence-based peptide encoding task. PepHarmony innovatively combines both sequence- and structure-level information into a sequence-level encoding module through contrastive learning. We carefully select datasets from the Protein Data Bank (PDB) and AlphaFold database to encompass a broad spectrum of peptide sequences and structures. The experimental data highlights PepHarmony's exceptional capability in capturing the intricate relationship between peptide sequences and structures compared with the baseline and fine-tuned models. The robustness of our model is confirmed through extensive ablation studies, which emphasize the crucial roles of contrastive loss and strategic data sorting in enhancing predictive performance. The proposed PepHarmony framework serves as a notable contribution to peptide representations, and offers valuable insights for future applications in peptide drug discovery and peptide engineering. We have made all the source code utilized in this study publicly accessible via GitHub at https://github.com/zhangruochi/PepHarmony or http://www.healthinformaticslab.org/supp/.

Kewei Li, Yuqian Wu, Yinheng Li et al.

Since the mechanism of action of drug molecules in the human body is difficult to reproduce in the in vitro environment, it becomes difficult to reveal the causes of the activity cliff phenomenon of drug molecules. We found out the AC of small molecules has been extensively investigated but limited knowledge is accumulated about the AC phenomenon in peptides with canonical amino acids. Understanding the mechanism of AC in canonical amino acids might help understand the one in drug molecules. This study introduces a quantitative definition and benchmarking framework AMPCliff for the AC phenomenon in antimicrobial peptides (AMPs) composed by canonical amino acids. A comprehensive analysis of the existing AMP dataset reveals a significant prevalence of AC within AMPs. AMPCliff quantifies the activities of AMPs by the MIC, and defines 0.9 as the minimum threshold for the normalized BLOSUM62 similarity score between a pair of aligned peptides with at least two-fold MIC changes. This study establishes a benchmark dataset of paired AMPs in Staphylococcus aureus from the publicly available AMP dataset GRAMPA, and conducts a rigorous procedure to evaluate various AMP AC prediction models, including nine machine learning, four deep learning algorithms, four masked language models, and four generative language models. Our analysis reveals that these models are capable of detecting AMP AC events and the pre-trained protein language model ESM2 demonstrates superior performance across the evaluations. The predictive performance of AMP activity cliffs remains to be further improved, considering that ESM2 with 33 layers only achieves the Spearman correlation coefficient 0.4669 for the regression task of the MIC values on the benchmark dataset. Source code and additional resources are available at https://www.healthinformaticslab.org/supp/ or https://github.com/Kewei2023/AMPCliff-generation.

Kewei Li, Yanwen Kong, Yiping Xu et al.

Since the emergence of research on improving the length extrapolation capabilities of large language models in 2021, some studies have made modifications to the scaling factor in the scaled dot-product attention mechanism as part of their proposed methods without rigorous theoretical justifications. To fill this gap, we propose two new scaled temperatures based on information entropy invariance to enhance length extrapolation. First, a training-free method InfoScale is designed for dotproduct attention, and preserves focus on original tokens during length extrapolation by ensuring consistent entropy. Second, we theoretically analyze the impact of scaling (CosScale) on cosine attention. Experimental data demonstrates that combining InfoScale and CosScale achieves state-ofthe-art performance on the GAU-α model with a context window extended to 64 times the training length, and outperforms seven existing methods. Our analysis reveals that significantly increasing CosScale approximates the Windowed Attention, and highlights the significance of attention score dilution as a key challenge in long-range context handling. The code and data are available at https://github.com/HT-NEKO/ Information-Entropy-Invariance.