دورية أكاديمية
Identification of Family-Specific Features in Cas9 and Cas12 Proteins: A Machine Learning Approach Using Complete Protein Feature Spectrum.
| العنوان: | Identification of Family-Specific Features in Cas9 and Cas12 Proteins: A Machine Learning Approach Using Complete Protein Feature Spectrum. |
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| المؤلفون: | Madugula SS; Department of Pharmaceutical Sciences, University of North Texas System College of Pharmacy, University of North Texas Health Science Center, 3500 Camp Bowie Blvd, Fort Worth, Texas 76107, United States., Pujar P; Department of Industrial, Manufacturing and Systems Engineering, University of Texas at Arlington, 701 South Nedderman Drive, Arlington, Texas 76019, United States., Nammi B; Department of Industrial, Manufacturing and Systems Engineering, University of Texas at Arlington, 701 South Nedderman Drive, Arlington, Texas 76019, United States., Wang S; Department of Industrial, Manufacturing and Systems Engineering, University of Texas at Arlington, 701 South Nedderman Drive, Arlington, Texas 76019, United States., Jayasinghe-Arachchige VM; Department of Pharmaceutical Sciences, University of North Texas System College of Pharmacy, University of North Texas Health Science Center, 3500 Camp Bowie Blvd, Fort Worth, Texas 76107, United States., Pham T; School of Biomedical Sciences, University of North Texas Health Science Center, 3500 Camp Bowie Blvd, Fort Worth, Texas 76107, United States., Mashburn D; Department of Pharmaceutical Sciences, University of North Texas System College of Pharmacy, University of North Texas Health Science Center, 3500 Camp Bowie Blvd, Fort Worth, Texas 76107, United States., Artiles M; School of Biomedical Sciences, University of North Texas Health Science Center, 3500 Camp Bowie Blvd, Fort Worth, Texas 76107, United States., Liu J; Department of Pharmaceutical Sciences, University of North Texas System College of Pharmacy, University of North Texas Health Science Center, 3500 Camp Bowie Blvd, Fort Worth, Texas 76107, United States.; School of Biomedical Sciences, University of North Texas Health Science Center, 3500 Camp Bowie Blvd, Fort Worth, Texas 76107, United States. |
| المصدر: | Journal of chemical information and modeling [J Chem Inf Model] 2024 Jun 24; Vol. 64 (12), pp. 4897-4911. Date of Electronic Publication: 2024 Jun 05. |
| نوع المنشور: | Journal Article |
| اللغة: | English |
| بيانات الدورية: | Publisher: American Chemical Society Country of Publication: United States NLM ID: 101230060 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1549-960X (Electronic) Linking ISSN: 15499596 NLM ISO Abbreviation: J Chem Inf Model Subsets: MEDLINE |
| أسماء مطبوعة: | Original Publication: Washington, D.C. : American Chemical Society, c2005- |
| مواضيع طبية MeSH: | Machine Learning* , CRISPR-Associated Protein 9*/chemistry , CRISPR-Associated Protein 9*/metabolism , CRISPR-Associated Protein 9*/genetics, CRISPR-Associated Proteins/chemistry ; CRISPR-Associated Proteins/metabolism ; CRISPR-Cas Systems |
| مستخلص: | The recent development of CRISPR-Cas technology holds promise to correct gene-level defects for genetic diseases. The key element of the CRISPR-Cas system is the Cas protein, a nuclease that can edit the gene of interest assisted by guide RNA. However, these Cas proteins suffer from inherent limitations such as large size, low cleavage efficiency, and off-target effects, hindering their widespread application as a gene editing tool. Therefore, there is a need to identify novel Cas proteins with improved editing properties, for which it is necessary to understand the underlying features governing the Cas families. In this study, we aim to elucidate the unique protein features associated with Cas9 and Cas12 families and identify the features distinguishing each family from non-Cas proteins. Here, we built Random Forest (RF) binary classifiers to distinguish Cas12 and Cas9 proteins from non-Cas proteins, respectively, using the complete protein feature spectrum (13,494 features) encoding various physiochemical, topological, constitutional, and coevolutionary information on Cas proteins. Furthermore, we built multiclass RF classifiers differentiating Cas9, Cas12, and non-Cas proteins. All the models were evaluated rigorously on the test and independent data sets. The Cas12 and Cas9 binary models achieved a high overall accuracy of 92% and 95% on their respective independent data sets, while the multiclass classifier achieved an F1 score of close to 0.98. We observed that Quasi-Sequence-Order (QSO) descriptors like Schneider.lag and Composition descriptors like charge, volume, and polarizability are predominant in the Cas12 family. Conversely Amino Acid Composition descriptors, especially Tripeptide Composition (TPC), predominate the Cas9 family. Four of the top 10 descriptors identified in Cas9 classification are tripeptides PWN, PYY, HHA, and DHI, which are seen to be conserved across all Cas9 proteins and located within different catalytically important domains of the Streptococcus pyogenes Cas9 (SpCas9) structure. Among these, DHI and HHA are well-known to be involved in the DNA cleavage activity of the SpCas9 protein. Mutation studies have highlighted the significance of the PWN tripeptide in PAM recognition and DNA cleavage activity of SpCas9, while Y450 from the PYY tripeptide plays a crucial role in reducing off-target effects and improving the specificity in SpCas9. Leveraging our machine learning (ML) pipeline, we identified numerous Cas9 and Cas12 family-specific features. These features offer valuable insights for future experimental and computational studies aiming at designing Cas systems with enhanced gene-editing properties. These features suggest plausible structural modifications that can effectively guide the development of Cas proteins with improved editing capabilities. |
| التعليقات: | Update of: bioRxiv. 2024 Jan 23:2024.01.22.576286. doi: 10.1101/2024.01.22.576286. (PMID: 38328240) |
| معلومات مُعتمدة: | R21 GM144860 United States GM NIGMS NIH HHS |
| المشرفين على المادة: | EC 3.1.- (CRISPR-Associated Protein 9) 0 (CRISPR-Associated Proteins) |
| تواريخ الأحداث: | Date Created: 20240605 Date Completed: 20240624 Latest Revision: 20240711 |
| رمز التحديث: | 20240711 |
| DOI: | 10.1021/acs.jcim.4c00625 |
| PMID: | 38838358 |
| قاعدة البيانات: | MEDLINE |
Find this issue from the American Chemical Society | تدمد: | 1549-960X |
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| DOI: | 10.1021/acs.jcim.4c00625 |