AMPGAN v2: Machine Learning-Guided Design of Antimicrobial Peptides.
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ABSTRACT:
SUBMITTER: Van Oort CM
PROVIDER: S-EPMC8281497 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Reducing hurdles to clinical trials without compromising the therapeutic promises of peptide candidates becomes an essential step in peptide-based drug design. Machine-learning models are cost-effective and time-saving strategies used to predict biological activities from primary sequences. Their limitations lie in the diversity of peptide sequences and biological information within these models. Additional outlier detection methods are needed to set the boundaries for reliable predictions; the applicability domain. Antimicrobial peptides (AMPs) constitute an extensive library of peptides offering promising avenues against antibiotic-resistant infections. Most AMPs present in clinical trials are administrated topically due to their hemolytic toxicity. Here we developed machine learning models and outlier detection methods that ensure robust predictions for the discovery of AMPs and the design of novel peptides with reduced hemolytic activity. Our best models, gradient boosting classifiers, predicted the hemolytic nature from any peptide sequence with 95-97% accuracy. Nearly 70% of AMPs were predicted as hemolytic peptides. Applying multivariate outlier detection models, we found that 273 AMPs (~ 9%) could not be predicted reliably. Our combined approach led to the discovery of 34 high-confidence non-hemolytic natural AMPs, the de novo design of 507 non-hemolytic peptides, and the guidelines for non-hemolytic peptide design.
| S-EPMC7538962 | biostudies-literature
Project description:Antimicrobial peptides (AMPs) are a diverse class of well-studied membrane-permeating peptides with important functions in innate host defense. In this short review, we provide a historical overview of AMPs, summarize previous applications of machine learning to AMPs, and discuss the results of our studies in the context of the latest AMP literature. Much work has been recently done in leveraging computational tools to design new AMP candidates with high therapeutic efficacies for drug-resistant infections. We show that machine learning on AMPs can be used to identify essential physico-chemical determinants of AMP functionality, and identify and design peptide sequences to generate membrane curvature. In a broader scope, we discuss the implications of our findings for the discovery of membrane-active peptides in general, and uncovering membrane activity in new and existing peptide taxonomies.
| S-EPMC5665795 | biostudies-literature
Project description:Machine learning (ML) consists of the recognition of patterns from training data and offers the opportunity to exploit large structure-activity databases for drug design. In the area of peptide drugs, ML is mostly being tested to design antimicrobial peptides (AMPs), a class of biomolecules potentially useful to fight multidrug-resistant bacteria. ML models have successfully identified membrane disruptive amphiphilic AMPs, however mostly without addressing the associated toxicity to human red blood cells. Here we trained recurrent neural networks (RNN) with data from DBAASP (Database of Antimicrobial Activity and Structure of Peptides) to design short non-hemolytic AMPs. Synthesis and testing of 28 generated peptides, each at least 5 mutations away from training data, allowed us to identify eight new non-hemolytic AMPs against Pseudomonas aeruginosa, Acinetobacter baumannii, and methicillin-resistant Staphylococcus aureus (MRSA). These results show that machine learning (ML) can be used to design new non-hemolytic AMPs.
| S-EPMC8285431 | biostudies-literature
Project description:IntroductionAntimicrobial peptides (AMPs) are promising alternatives to traditional antibiotics for combating plant pathogenic bacteria in agriculture and the environment. However, identifying potent AMPs through laborious experimental assays is resource-intensive and time-consuming. To address these limitations, this study presents a bioinformatics approach utilizing machine learning models for predicting and selecting AMPs active against plant pathogenic bacteria.MethodsN-gram representations of peptide sequences with 3-letter and 9-letter reduced amino acid alphabets were used to capture the sequence patterns and motifs that contribute to the antimicrobial activity of AMPs. A 5-fold cross-validation technique was used to train the machine learning models and to evaluate their predictive accuracy and robustness.ResultsThe models were applied to predict putative AMPs encoded by intergenic regions and small open reading frames (ORFs) of the citrus genome. Approximately 7% of the 10,000-peptide dataset from the intergenic region and 7% of the 685,924-peptide dataset from the whole genome were predicted as probable AMPs. The prediction accuracy of the reported models range from 0.72 to 0.91. A subset of the predicted AMPs was selected for experimental test against Spiroplasma citri, the causative agent of citrus stubborn disease. The experimental results confirm the antimicrobial activity of the selected AMPs against the target bacterium, demonstrating the predictive capability of the machine learning models.DiscussionHydrophobic amino acid residues and positively charged amino acid residues are among the key features in predicting AMPs by the Random Forest Algorithm. Aggregation propensity appears to be correlated with the effectiveness of the AMPs. The described models would contribute to the development of effective AMP-based strategies for plant disease management in agricultural and environmental settings. To facilitate broader accessibility, our model is publicly available on the AGRAMP (Agricultural Ngrams Antimicrobial Peptides) server.
| S-EPMC10955071 | biostudies-literature
Project description:BackgroundInfectious diseases not only cause severe health problems but also burden the healthcare system. Therefore, the effective treatment of those diseases is crucial. Both conventional approaches, such as antimicrobial agents, and novel approaches, like antimicrobial peptides (AMPs), are used to treat infections. However, due to the drawbacks of current approaches, new solutions are still being investigated. One recent approach is the use of AMPs and antimicrobial agents in combination, but determining synergism is with a huge variety of AMPs time-consuming and requires multiple experimental studies. Machine learning (ML) algorithms are widely used to predict biological outcomes, particularly in the field of AMPs, but no previous research reported on predicting the synergistic effects of AMPs and antimicrobial agents.ResultsSeveral supervised ML models were implemented to accurately predict the synergistic effect of AMPs and antimicrobial agents. The results demonstrated that the hyperparameter-optimized Light Gradient Boosted Machine Classifier (oLGBMC) yielded the best test accuracy of 76.92% for predicting the synergistic effect. Besides, the feature importance analysis reveals that the target microbial species, the minimum inhibitory concentrations (MICs) of the AMP and the antimicrobial agents, and the used antimicrobial agent were the most important features for the prediction of synergistic effect, which aligns with recent experimental studies in the literature.ConclusionThis study reveals that ML algorithms can predict the synergistic activity of two different antimicrobial agents without the need for complex and time-consuming experimental procedures. The implications support that the ML models may not only reduce the experimental cost but also provide validation of experimental procedures.
| S-EPMC10792927 | biostudies-literature
Project description:BackgroundCurrent methods in machine learning provide approaches for solving challenging, multiple constraint design problems. While deep learning and related neural networking methods have state-of-the-art performance, their vulnerability in decision making processes leading to irrational outcomes is a major concern for their implementation. With the rising antibiotic resistance, antimicrobial peptides (AMPs) have increasingly gained attention as novel therapeutic agents. This challenging design problem requires peptides which meet the multiple constraints of limiting drug-resistance in bacteria, preventing secondary infections from imbalanced microbial flora, and avoiding immune system suppression. AMPs offer a promising, bioinspired design space to targeting antimicrobial activity, but their versatility also requires the curated selection from a combinatorial sequence space. This space is too large for brute-force methods or currently known rational design approaches outside of machine learning. While there has been progress in using the design space to more effectively target AMP activity, a widely applicable approach has been elusive. The lack of transparency in machine learning has limited the advancement of scientific knowledge of how AMPs are related among each other, and the lack of general applicability for fully rational approaches has limited a broader understanding of the design space.MethodsHere we combined an evolutionary method with rough set theory, a transparent machine learning approach, for designing antimicrobial peptides (AMPs). Our method achieves the customization of AMPs using supervised learning boundaries. Our system employs in vitro bacterial assays to measure fitness, codon-representation of peptides to gain flexibility of sequence selection in DNA-space with a genetic algorithm and machine learning to further accelerate the process.ResultsWe use supervised machine learning and a genetic algorithm to find a peptide active against S. epidermidis, a common bacterial strain for implant infections, with an improved aggregation propensity average for an improved ease of synthesis.ConclusionsOur results demonstrate that AMP design can be customized to maintain activity and simplify production. To our knowledge, this is the first time when codon-based genetic algorithms combined with rough set theory methods is used for computational search on peptide sequences.
| S-EPMC8111958 | biostudies-literature
Project description:Recent discoveries of extreme cellular diversity in the brain warrant rapid development of technologies to access specific cell populations, enabling characterization of their roles in behavior and in disease states. Available approaches for engineering targeted technologies for new neuron subtypes are low-yield, involving intensive transgenic strain or virus screening. Here, we introduce SNAIL (Specific Nuclear-Anchored Independent Labeling), a new virus-based strategy for cell labeling and nuclear isolation from heterogeneous tissue. SNAIL works by leveraging machine learning and other computational approaches to identify DNA sequence features that confer cell type-specific gene activation and using them to make a probe that drives an affinity purification-compatible reporter gene. As a proof of concept, we designed and validated two novel SNAIL probes that target parvalbumin-expressing (PV) neurons. Furthermore, we show that nuclear isolation using SNAIL in wild type mice is sufficient to capture characteristic open chromatin features of PV neurons in the cortex, striatum, and external globus pallidus. Expansion of this technology has broad applications in cell type-specific observation, manipulation, and therapeutics across species and disease models.
2021-06-01 | GSE171549 | GEO
Project description:We developed ML-based methods to optimize PE design
2021-07-26 | GSE175955 | GEO
Project description:Optimization of gene expression levels is an essential part of the organism design process. Fine control of this process can be achieved by engineering transcription and translation control elements, including the ribosome binding site (RBS). Unfortunately, the design of specific genetic parts remains challenging because of the lack of reliable design methods. To address this problem, we have created a machine learning guided Design-Build-Test-Learn (DBTL) cycle for the experimental design of bacterial RBSs to demonstrate how small genetic parts can be reliably designed using relatively small, high-quality data sets. We used Gaussian Process Regression for the Learn phase of the cycle and the Upper Confidence Bound multiarmed bandit algorithm for the Design of genetic variants to be tested in vivo. We have integrated these machine learning algorithms with laboratory automation and high-throughput processes for reliable data generation. Notably, by Testing a total of 450 RBS variants in four DBTL cycles, we have experimentally validated RBSs with high translation initiation rates equaling or exceeding our benchmark RBS by up to 34%. Overall, our results show that machine learning is a powerful tool for designing RBSs, and they pave the way toward more complicated genetic devices.
| S-EPMC9295160 | biostudies-literature
Project description:The discovery of peptides possessing high biological activity is very challenging due to the enormous diversity for which only a minority have the desired properties. To lower cost and reduce the time to obtain promising peptides, machine learning approaches can greatly assist in the process and even partly replace expensive laboratory experiments by learning a predictor with existing data or with a smaller amount of data generation. Unfortunately, once the model is learned, selecting peptides having the greatest predicted bioactivity often requires a prohibitive amount of computational time. For this combinatorial problem, heuristics and stochastic optimization methods are not guaranteed to find adequate solutions. We focused on recent advances in kernel methods and machine learning to learn a predictive model with proven success. For this type of model, we propose an efficient algorithm based on graph theory, that is guaranteed to find the peptides for which the model predicts maximal bioactivity. We also present a second algorithm capable of sorting the peptides of maximal bioactivity. Extensive analyses demonstrate how these algorithms can be part of an iterative combinatorial chemistry procedure to speed up the discovery and the validation of peptide leads. Moreover, the proposed approach does not require the use of known ligands for the target protein since it can leverage recent multi-target machine learning predictors where ligands for similar targets can serve as initial training data. Finally, we validated the proposed approach in vitro with the discovery of new cationic antimicrobial peptides. Source code freely available at http://graal.ift.ulaval.ca/peptide-design/.
| S-EPMC4388847 | biostudies-literature