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Protein Design and Protein Engineering
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Protein Design and Protein Engineering

A special issue of Molecules (ISSN 1420-3049). This special issue belongs to the section "Bioorganic Chemistry".

Deadline for manuscript submissions: closed (31 December 2023) | Viewed by 9717

Special Issue Editor

Dr. Xiaoqiang Huang

E-Mail Website
Guest Editor
Department of Internal Medicine, University of Michigan, 2800 Plymouth Rd, Ann Arbor, MI 48109, USA
Interests: computational protein design; protein–protein interaction; protein engineering; enzyme design and engineering; gene editing

Special Issue Information

Dear Colleagues,

In recent years, great progress has been witnessed on protein science and technology, especially after the most advanced artificial intelligence (AI) techniques were introduced into the protein field. For instance, DeepMind’s AlphaFold2 AI has almost solved the 50-year-old grand challenge—protein folding—in biology. Conversely, protein design and protein engineering, the techniques by which protein with enhanced or novel functional properties are generated, also benefit significantly from AI-based scientific and technological progress recently. Though the AI approaches are exciting and encouraging, great challenges still exist, and the traditional experimental, empirical, and computational protein design and engineering techniques are still quite helpful. We create this Special Issue in Molecules to call for research and review articles on any topic related to protein design and protein engineering.

Dr. Xiaoqiang Huang
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Molecules is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2700 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • protein design
  • protein engineering
  • protein structure prediction
  • artificial intelligence
  • machine learning
  • deep learning

Published Papers (6 papers)

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Research

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14 pages, 4042 KiB  
Article
Prediction of Thermostability of Enzymes Based on the Amino Acid Index (AAindex) Database and Machine Learning
by Gaolin Li, Lili Jia, Kang Wang, Tingting Sun and Jun Huang
Molecules 2023, 28(24), 8097; https://doi.org/10.3390/molecules28248097 - 15 Dec 2023
Viewed by 1239
Abstract
The combination of wet-lab experimental data on multi-site combinatorial mutations and machine learning is an innovative method in protein engineering. In this study, we used an innovative sequence-activity relationship (innov’SAR) methodology based on novel descriptors and digital signal processing (DSP) to construct a [...] Read more.
The combination of wet-lab experimental data on multi-site combinatorial mutations and machine learning is an innovative method in protein engineering. In this study, we used an innovative sequence-activity relationship (innov’SAR) methodology based on novel descriptors and digital signal processing (DSP) to construct a predictive model. In this paper, 21 experimental (R)-selective amine transaminases from Aspergillus terreus (AT-ATA) were used as an input to predict higher thermostability mutants than those predicted using the existing data. We successfully improved the coefficient of determination (R2) of the model from 0.66 to 0.92. In addition, root-mean-squared deviation (RMSD), root-mean-squared fluctuation (RMSF), solvent accessible surface area (SASA), hydrogen bonds, and the radius of gyration were estimated based on molecular dynamics simulations, and the differences between the predicted mutants and the wild-type (WT) were analyzed. The successful application of the innov’SAR algorithm in improving the thermostability of AT-ATA may help in directed evolutionary screening and open up new avenues for protein engineering. Full article
(This article belongs to the Special Issue Protein Design and Protein Engineering)
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18 pages, 2529 KiB  
Article
Engineering a New IFN-ApoA-I Fusion Protein with Low Toxicity and Prolonged Action
by Svetlana Miroshnichenko, Mariya Pykhtina, Anastasiia Kotliarova, Alexander Chepurnov and Anatoly Beklemishev
Molecules 2023, 28(24), 8014; https://doi.org/10.3390/molecules28248014 - 8 Dec 2023
Viewed by 1084
Abstract
Recombinant human interferon alpha-2b (rIFN) is widely used in antiviral and anticancer immunotherapy. However, the high efficiency of interferon therapy is accompanied by a number of side effects; this problem requires the design of a new class of interferon molecules with reduced cytotoxicity. [...] Read more.
Recombinant human interferon alpha-2b (rIFN) is widely used in antiviral and anticancer immunotherapy. However, the high efficiency of interferon therapy is accompanied by a number of side effects; this problem requires the design of a new class of interferon molecules with reduced cytotoxicity. In this work, IFN was modified via genetic engineering methods by merging it with the blood plasma protein apolipoprotein A-I in order to reduce acute toxicity and improve the pharmacokinetics of IFN. The chimeric protein was obtained via biosynthesis in the yeast P. pastoris. The yield of ryIFN-ApoA-I protein when cultivated on a shaker in flasks was 30 mg/L; protein purification was carried out using reverse-phase chromatography to a purity of 95–97%. The chimeric protein demonstrated complete preservation of the biological activity of IFN in the model of vesicular stomatitis virus and SARS-CoV-2. In addition, the chimeric form had reduced cytotoxicity towards Vero cells and increased cell viability under viral load conditions compared with commercial IFN-a2b preparations. Analysis of the pharmacokinetic profile of ryIFN-ApoA-I after a single subcutaneous injection in mice showed a 1.8-fold increased half-life of the chimeric protein compared with ryIFN. Full article
(This article belongs to the Special Issue Protein Design and Protein Engineering)
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17 pages, 8865 KiB  
Article
Construction of a Collagen-like Protein Based on Elastin-like Polypeptide Fusion and Evaluation of Its Performance in Promoting Wound Healing
by Yingli Chen, Yuanyuan Wu, Fengmin Xiong, Wei Yu, Tingting Wang, Jingjing Xiong, Luping Zhou, Fei Hu, Xianlong Ye and Xinmiao Liang
Molecules 2023, 28(19), 6773; https://doi.org/10.3390/molecules28196773 - 23 Sep 2023
Cited by 2 | Viewed by 1353
Abstract
In the healing of wounds, human-like collagen (hCol) is essential. However, collagen-based composite dressings have poor stability in vivo, which severely limits their current therapeutic potential. Based on the above, we have developed a recombinant fusion protein named hCol-ELP, which consists of hCol [...] Read more.
In the healing of wounds, human-like collagen (hCol) is essential. However, collagen-based composite dressings have poor stability in vivo, which severely limits their current therapeutic potential. Based on the above, we have developed a recombinant fusion protein named hCol-ELP, which consists of hCol and an elastin-like peptide (ELP). Then, we examined the physicochemical and biological properties of hCol-ELP. The results indicated that the stability of the hCol-ELP fusion protein exhibited a more compact and homogeneous lamellar microstructure along with collagen properties, it was found to be significantly superior to the stability of free hCol. The compound hCol-ELP demonstrated a remarkable capacity to induce the proliferation and migration of mouse embryo fibroblast cells (NIH/3T3), as well as enhance collagen synthesis in human skin fibroblasts (HSF) when tested in vitro. In vivo, hCol-ELP demonstrated significant enhancements in healing rate and a reduction in the time required for scab removal, thereby exhibiting a scar-free healing effect. The findings provide a crucial theoretical foundation for the implementation of an hCol-ELP protein dressing in fields associated with the healing of traumatic injuries. Full article
(This article belongs to the Special Issue Protein Design and Protein Engineering)
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17 pages, 3732 KiB  
Article
Modulating Substrate Specificity of Rhizobium sp. Histamine Dehydrogenase through Protein Engineering for Food Quality Applications
by Karen Rodríguez-Núñez, Alejandra Cortés-Monroy, Marcela Serey, Yunus Ensari, Mehdi D. Davari, Claudia Bernal and Ronny Martinez
Molecules 2023, 28(9), 3748; https://doi.org/10.3390/molecules28093748 - 26 Apr 2023
Cited by 2 | Viewed by 2030
Abstract
Histamine is a biogenic amine found in fish-derived and fermented food products with physiological relevance since its concentration is proportional to food spoilage and health risk for sensitive consumers. There are various analytical methods for histamine quantification from food samples; however, a simple [...] Read more.
Histamine is a biogenic amine found in fish-derived and fermented food products with physiological relevance since its concentration is proportional to food spoilage and health risk for sensitive consumers. There are various analytical methods for histamine quantification from food samples; however, a simple and quick enzymatic detection and quantification method is highly desirable. Histamine dehydrogenase (HDH) is a candidate for enzymatic histamine detection; however, other biogenic amines can change its activity or produce false positive results with an observed substrate inhibition at higher concentrations. In this work, we studied the effect of site saturation mutagenesis in Rhizobium sp. Histamine Dehydrogenase (Rsp HDH) in nine amino acid positions selected through structural alignment analysis, substrate docking, and proximity to the proposed histamine-binding site. The resulting libraries were screened for histamine and agmatine activity. Variants from two libraries (positions 72 and 110) showed improved histamine/agmatine activity ratio, decreased substrate inhibition, and maintained thermal resistance. In addition, activity characterization of the identified Phe72Thr and Asn110Val HDH variants showed a clear substrate inhibition curve for histamine and modified kinetic parameters. The observed maximum velocity (Vmax) increased for variant Phe72Thr at the cost of an increased value for the Michaelis–Menten constant (Km) for histamine. The increased Km value, decreased substrate inhibition, and biogenic amine interference observed for variant Phe72Thr support a tradeoff between substrate affinity and substrate inhibition in the catalytic mechanism of HDHs. Considering this tradeoff for future enzyme engineering of HDH could lead to breakthroughs in performance increases and understanding of this enzyme class. Full article
(This article belongs to the Special Issue Protein Design and Protein Engineering)
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Review

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15 pages, 3358 KiB  
Review
The Versatile Biocatalyst of Cytochrome P450 CYP102A1: Structure, Function, and Engineering
by Yudong Sun, Xiaoqiang Huang, Yoichi Osawa, Yuqing Eugene Chen and Haoming Zhang
Molecules 2023, 28(14), 5353; https://doi.org/10.3390/molecules28145353 - 12 Jul 2023
Cited by 1 | Viewed by 1721
Abstract
Wild-type cytochrome P450 CYP102A1 from Bacillus megaterium is a highly efficient monooxygenase for the oxidation of long-chain fatty acids. The unique features of CYP102A1, such as high catalytic activity, expression yield, regio- and stereoselectivity, and self-sufficiency in electron transfer as a fusion protein, [...] Read more.
Wild-type cytochrome P450 CYP102A1 from Bacillus megaterium is a highly efficient monooxygenase for the oxidation of long-chain fatty acids. The unique features of CYP102A1, such as high catalytic activity, expression yield, regio- and stereoselectivity, and self-sufficiency in electron transfer as a fusion protein, afford the requirements for an ideal biocatalyst. In the past three decades, remarkable progress has been made in engineering CYP102A1 for applications in drug discovery, biosynthesis, and biotechnology. The repertoire of engineered CYP102A1 variants has grown tremendously, whereas the substrate repertoire is avalanched to encompass alkanes, alkenes, aromatics, organic solvents, pharmaceuticals, drugs, and many more. In this article, we highlight the major advances in the past five years in our understanding of the structure and function of CYP102A1 and the methodologies used to engineer CYP102A1 for novel applications. The objective is to provide a succinct review of the latest developments with reference to the body of CYP102A1-related literature. Full article
(This article belongs to the Special Issue Protein Design and Protein Engineering)
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18 pages, 1729 KiB  
Review
Recent Advances in β-Glucosidase Sequence and Structure Engineering: A Brief Review
by Bei Ouyang, Guoping Wang, Nian Zhang, Jiali Zuo, Yunhong Huang and Xihua Zhao
Molecules 2023, 28(13), 4990; https://doi.org/10.3390/molecules28134990 - 25 Jun 2023
Cited by 8 | Viewed by 1781
Abstract
β-glucosidases (BGLs) play a crucial role in the degradation of lignocellulosic biomass as well as in industrial applications such as pharmaceuticals, foods, and flavors. However, the application of BGLs has been largely hindered by issues such as low enzyme activity, product inhibition, low [...] Read more.
β-glucosidases (BGLs) play a crucial role in the degradation of lignocellulosic biomass as well as in industrial applications such as pharmaceuticals, foods, and flavors. However, the application of BGLs has been largely hindered by issues such as low enzyme activity, product inhibition, low stability, etc. Many approaches have been developed to engineer BGLs to improve these enzymatic characteristics to facilitate industrial production. In this article, we review the recent advances in BGL engineering in the field, including the efforts from our laboratory. We summarize and discuss the BGL engineering studies according to the targeted functions as well as the specific strategies used for BGL engineering. Full article
(This article belongs to the Special Issue Protein Design and Protein Engineering)
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