Article
Chemistry, Physical
Andrea Rizzi, Paolo Carloni, Michele Parrinello
Summary: The method presented extends the theory of targeted free energy perturbation to accurately calculate free energy differences and surfaces at a quantum mechanical level from a cheaper reference potential. Accelerated convergence is achieved by increasing the overlap between target and reference distributions. The method is validated through numerical evaluations in different systems, demonstrating its effectiveness in avoiding systematic errors.
JOURNAL OF PHYSICAL CHEMISTRY LETTERS
(2021)
Article
Chemistry, Physical
Mercedes Alfonso-Prieto, Irene Cuxart, Gabrielle Potocki-Veronese, Isabelle Andre, Carme Rovira
Summary: The unknown human gut bacterium mannoside phosphorylase (UhgbMP) plays a role in metabolizing eukaryotic N-glycans in the intestinal epithelium and is associated with inflammatory bowel diseases. Quantum mechanics/molecular mechanics metadynamics study reveals that UhgbMP operates through substrate-assisted catalysis via the 3-hydroxyl group of the mannosyl unit. This mechanism is expected to be applicable to other GH130 enzymes and provides insights for the design of specific inhibitors.
Article
Chemistry, Physical
Martin Calvelo, Alexandra Males, Matthew G. Alteen, Lianne I. Willems, David J. Vocadlo, Gideon J. Davies, Carme Rovira
Summary: This study reports the crystal structure of human O-linked beta-N-acetylglucosaminidase (hOGA) and elucidates its catalytic mechanism using QM/MM metadynamics. The enzyme can bind the substrate in either a chair- or a boat-like conformation, but only the latter is catalytically competent. These findings will aid in the development of more effective inhibitors for diseases associated with impaired O-GlcNAcylation.
Article
Biochemistry & Molecular Biology
De-Fa Rao, Hui Zhang, Ju-Ling Wang, Xiao-Xiao Meng, Zhen-Zhen Li, Chun-Ya Xie, Ikrame El Jaidi, Li Dai, Jing-Jing Ye, Min Zhu, Yu-Jie Peng, Qi Chen, Dao-Xiang Zhang, Yan-Bin Teng
Summary: The O-carbamoyltransferase VtdB is crucial for the biosynthesis of the antibiotic venturicidin A as it catalyzes the carbamoylation of venturicidin B. This study determined the crystal structures of VtdB and VtdB in complex with the intermediate carbamoyladenylate. The structures exhibit conserved YrdC-like and specific Kae1-like domains, and a novel venturicidin B binding pocket was revealed.
BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS
(2023)
Article
Biochemistry & Molecular Biology
Soukayna Baammi, Rachid Daoud, Achraf El Allali
Summary: This study investigates the impact of 30 mutations on the activity and stability of phosphite dehydrogenase (PTDH) using molecular docking, molecular dynamics (MD) simulation, and Quantum Mechanics/Molecular Mechanics (QM/MM). The results reveal the effects of the mutations on the NAD(+) binding site, phosphite oxidation, and structural dynamics of PTDH. The findings provide specific explanations on how mutations affect weak interactions of PTDH.
JOURNAL OF BIOMOLECULAR STRUCTURE & DYNAMICS
(2023)
Article
Engineering, Environmental
Mingna Zheng, Yanwei Li, Weiliang Dong, Shanshan Feng, Qingzhu Zhang, Wenxing Wang
Summary: Four concerted steps are needed to complete the catalytic cycle of PET biotransformation by leaf-branch compost cutinase (LCC), with deacylation identified as the rate-determining step. Unprecedented fluctuations of hydrogen bond length were observed during LCC catalyzed transformation process toward PET, indicating a potential widespread phenomenon in enzymes containing catalytic triads. Possible features influencing the catalytic reaction were identified, establishing correlations between activation energies and key features.
JOURNAL OF HAZARDOUS MATERIALS
(2022)
Article
Chemistry, Physical
Edoardo Cignoni, Lorenzo Cupellini, Benedetta Mennucci
Summary: We propose a machine learning strategy to calculate the excitonic properties of light harvesting complexes. By combining molecular dynamics simulations with ML prediction of the excitonic Hamiltonian, the proposed model can account for geometric fluctuations and electrostatic interactions. The model is trained on chlorophylls but can extrapolate beyond the training set, and its accuracy is demonstrated through simulations of absorption spectra in different environments.
JOURNAL OF CHEMICAL THEORY AND COMPUTATION
(2023)
Article
Green & Sustainable Science & Technology
Mingna Zheng, Yanwei Li, Weiliang Dong, Jie Shen, Qingzhu Zhang
Summary: The degradation mechanism of PE oligomer by P450 BM3 variant was explored using molecular dynamics simulations and quantum mechanics/molecular mechanics calculations. It was found that the degradation involves hydrogen abstraction and rebound processes, with hydrogen abstraction being the rate-determining step. The study also revealed regio- and stereoselectivity during the degradation process, and identified key structural parameters that greatly influence PE degradation efficiency. The degradation process of PVC oligomer was also investigated, showing differences in the catalytic energy landscape compared to PE oligomer. Overall, these findings provide an environmentally friendly strategy for the removal of PE and PVC waste.
JOURNAL OF CLEANER PRODUCTION
(2023)
Article
Chemistry, Physical
Beatriz Piniello, Erandi Lira-Navarrete, Hideyuki Takeuchi, Megumi Takeuchi, Robert S. Haltiwanger, Ramon Hurtado-Guerrero, Carme Rovira
Summary: O-glycosylation is essential for life and involves enzymes like POFUT1, which fucosylates specific residues in EGF-LD. POFUT1 lacks a catalytic base in its active site, but uses a mechanism involving proton shuttling through a conserved asparagine residue. Mutations in this residue can abolish enzyme activity, providing insights for developing inhibitors for O-glycosylation disorders.
Article
Biochemistry & Molecular Biology
Zijian Wang, Qingzhu Zhang, Guoqiang Wang, Wenxing Wang, Qiao Wang
Summary: This study systematically investigated the hydrolysis mechanism of methomyl catalyzed by esterase PestE. The results provided atomic-level details of the mechanism and free energy profiles. Serine-initiated nucleophilic attack was identified as the rate-determining step, and the importance of protein-substrate interactions and key active site residues was elucidated.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2023)
Article
Physics, Multidisciplinary
Manyi Yang, Tarak Karmakar, Michele Parrinello
Summary: The study focuses on the liquid-liquid phase transition of phosphorus, with the determination of a first-order phase transition and the observation of large fluctuations in the vicinity of the second-order critical point.
PHYSICAL REVIEW LETTERS
(2021)
Article
Chemistry, Physical
Yazdan Maghsoud, Chao Dong, G. Andres Cisneros
Summary: In this study, the inhibition mechanism of Xanthine oxidase (XO) and a new promising drug, topiroxostat (code: FYX-051), was investigated using molecular dynamics (MD) and quantum mechanics/molecular mechanics (QM/MM) calculations. The results showed that topiroxostat acts as a noncovalent and covalent inhibitor, with its hydroxylated metabolites inhibiting XO in a stepwise manner. The study provides insights into the detailed inhibition mechanism of each metabolite, which can be useful for designing more effective drugs targeting XO.
Article
Chemistry, Applied
Pramod Kumar, Vijay Kumar Bhardwaj, Rituraj Purohit
Summary: This study examined the stability of Chrysin (ChR) inside cyclodextrins (CDs) by forming inclusion complexes with three forms of CDs (alpha-, beta-, and gamma-CD). The aim was to find the most suitable CD form to improve the hydro-solubility of ChR. Molecular dynamics simulations were performed on the complexes to study the dynamics of ChR inside the cavity of CDs. The results showed that the gamma-CD1/ChR complex had the highest affinity, making gamma-CD a suitable host molecule for improving the hydro-solubility of ChR.
CARBOHYDRATE POLYMERS
(2023)
Article
Chemistry, Multidisciplinary
Laura Zanetti-Polzi, Patrick Charchar, Irene Yarovsky, Stefano Corni
Summary: Through theoretical investigation, we have revealed the impact of peptide-ligand environment on the pH-responsive fluorescence of gold nanoclusters. Our findings show that subtle changes in the hexapeptide sequence can significantly alter the pH response of the clusters, providing insights into the underlying mechanism.
Article
Chemistry, Physical
Temitope Isaac Adelusi, Abdul-Quddus Kehinde Oyedele, Ojo Emmanuel Monday, Ibrahim Damilare Boyenle, Mukhtar Oluwaseun Idris, Abdeen Tunde Ogunlana, Ashiru Mojeed Ayoola, John Olabode Fatoki, Oladipo Elijah Kolawole, Kehinde Busuyi David, Akintola Adebola Olayemi
Summary: The study investigated the inhibitory potential of fifty dietary polyphenols against the main protease of the SARS-like Coronavirus. Among them, Ellagic acid, Kievitone, and Punicalin showed promising binding affinities, while further analysis suggested punicalin may have adverse effects in clinical trials.
JOURNAL OF MOLECULAR STRUCTURE
(2022)
Article
Chemistry, Physical
Sergi Roda, Laura Fernandez-Lopez, Ruben Canadas, Gerard Santiago, Manuel Ferrer, Victor Guallar
Summary: Through studying enzymes with narrow substrate spectra, it was demonstrated that active site parameters can be manipulated to alter substrate specificity and design new enzyme variants with broader substrate promiscuity.
Article
Chemistry, Multidisciplinary
David Ribeaucourt, Bastien Bissaro, Victor Guallar, Mehdi Yemloul, Mireille Haon, Sacha Grisel, Veronique Alphand, Harry Brumer, Fanny Lambert, Jean-Guy Berrin, Mickael Lafond
Summary: The oxidation of alcohols is crucial in chemistry, particularly in the flavor and fragrance industry. Biocatalysis, especially using enzymes like alcohol oxidase from Colletotrichum graminicola, shows promise in converting long-chain aliphatic alcohols to aldehydes. Controlling reaction conditions can tune the distribution of aldehyde and acid products, making fungal CRO-AlcOx a potential candidate for green production of flavor and fragrance compounds.
ACS SUSTAINABLE CHEMISTRY & ENGINEERING
(2021)
Article
Chemistry, Physical
Sergi Roda, Ana Robles-Martin, Ruite Xiang, Masoud Kazemi, Victor Guallar
Summary: The importance of biotechnological solutions in our future society is highlighted, with enzyme engineering being a key aspect for waste transformation and clean energy production. Structural-based bioinformatics and molecular modeling tools play a crucial role in these developments.
JOURNAL OF PHYSICAL CHEMISTRY B
(2021)
Article
Virology
Benjamin Trinite, Edwards Pradenas, Silvia Marfil, Carla Rovirosa, Victor Urrea, Ferran Tarres-Freixas, Raquel Ortiz, Jordi Rodon, Julia Vergara-Alert, Joaquim Segales, Victor Guallar, Rosalba Lepore, Nuria Izquierdo-Useros, Gloria Trujillo, Jaume Trape, Carolina Gonzalez-Fernandez, Antonia Flor, Rafel Perez-Vidal, Ruth Toledo, Anna Chamorro, Roger Paredes, Ignacio Blanco, Eulalia Grau, Marta Massanella, Jorge Carrillo, Bonaventura Clotet, Julia Blanco
Summary: The study found that the time from natural infection and the nature of the infecting variant determined cross-neutralization; Uninfected vaccinees showed a small reduction in neutralization against the B.1.1.7 variant; Previously infected individuals developed more robust neutralizing responses against B.1.1.7 after vaccination, indicating that vaccines can enhance the neutralization breadth conferred by natural infection.
Article
Chemistry, Physical
Julia J. Liang, Eleni Pitsillou, Katherine Ververis, Victor Guallar, Andrew Hung, Tom C. C. Karagiannis
Summary: This study finds that hypericin may have antiviral effects against SARS-CoV-2 by inhibiting viral replication through binding to the PLpro protease. Although less potent than the known inhibitor GRL-0617, hypericin still shows inhibitory effects on the protease and deubiquitinating activities of PLpro.
CHEMICAL PHYSICS LETTERS
(2022)
Article
Biochemistry & Molecular Biology
Alessandro Boverio, Wahyu S. Widodo, Lars L. Santema, Henriette J. Rozeboom, Ruite Xiang, Victor Guallar, Andrea Mattevi, Marco W. Fraaije
Summary: In this study, the newly discovered carbohydrate oxidase NagOx from Ralstonia solanacearum was biochemically and structurally characterized. It showed high activity towards N-acetyl-D-galactosamine and N-acetyl-D-glucosamine, and could accept non-acetylated hexoses with lower efficiency. The crystal structure revealed a FAD-bound cavity and substrate docking highlighted a key residue involved in the accommodation of N-acetylated sugars. An enzyme variant with modified substrate acceptance profile was generated by replacing this residue. NagOx, being overexpressed in a bacterial host, has potential as a customizable biocatalyst for selective oxidation of monosaccharides and oligosaccharides.
Article
Biochemistry & Molecular Biology
Laura Fernandez-Lopez, Sergi Roda, Jose L. Gonzalez-Alfonso, Francisco J. Plou, Victor Guallar, Manuel Ferrer
Summary: In this study, a catalytically efficient artificial protease was designed and easily produced. By modifying an esterase site, a proteolytic site was successfully created. The resulting artificial enzyme exhibited efficient hydrolysis activity under suitable conditions and could be used for one-pot cascade synthesis reactions.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2022)
Article
Chemistry, Medicinal
Thijs Beuming, Helena Martin, Anna M. Diaz-Rovira, Lucia Diaz, Victor Guallar, Soumya S. Ray
Summary: The availability of AlphaFold2 has generated excitement in the scientific community, especially among drug researchers, due to its high accuracy in predicting protein structures. This study explores whether the predicted structures by AlphaFold2 are accurate enough to be useful in computationally driven drug discovery programs, specifically in predicting ligand binding sites. The findings suggest that, under certain circumstances, AlphaFold2-modeled structures can be used with physics-based methods, such as free energy perturbation, in the lead optimization stages of drug discovery programs.
JOURNAL OF CHEMICAL INFORMATION AND MODELING
(2022)
Article
Biochemistry & Molecular Biology
Ruite Xiang, Laura Fernandez-Lopez, Ana Robles-Martin, Manuel Ferrer, Victor Guallar
Summary: Substrate promiscuity is a desirable property that increases the reusability of enzymes, but finding new substrate promiscuous ester hydrolases is challenging. We have developed a method called EP-pred, which can predict promiscuity from sequence alone and successfully identified ten sequences encoding promiscuous esterases.
Review
Biochemistry & Molecular Biology
Ignasi Puch-Giner, Alexis Molina, Marti Municoy, Carles Perez, Victor Guallar
Summary: Computer simulation techniques are becoming increasingly important in molecular pharmacology. This review summarizes recent efforts in this direction, focusing on the unconventional Monte Carlo PELE software and its combination with machine learning techniques. New data on combining aquaPELE and fragPELE techniques are also provided for fragment growing and exhaustive water sampling.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2022)
Review
Chemistry, Multidisciplinary
Carles Perez-Lopez, Alexis Molina, Estrella Lozoya, Victor Segarra, Marti Municoy, Victor Guallar
Summary: Machine learning techniques provide a new and exciting approach in the field of drug discovery, potentially surpassing traditional molecular mechanics modeling methods. This review article advocates for the combination of both techniques to achieve the most efficient implementation in the coming years. It discusses pure machine learning approaches and recent developments in integrating machine learning with molecular mechanics methods, as well as presents a real industrial prospective study showcasing the successful combination of Monte Carlo molecular mechanics simulations with machine learning for drug-target affinity predictions.
WILEY INTERDISCIPLINARY REVIEWS-COMPUTATIONAL MOLECULAR SCIENCE
(2023)
Article
Chemistry, Multidisciplinary
Xiaomin Xu, Jacob M. A. van Hengst, Yejia Mao, Mireia Martinez, Sergi Roda, Martin Floor, Victor Guallar, Caroline E. Paul, Miguel Alcalde, Frank Hollmann
Summary: A peroxygenase-catalysed hydroxylation of organosilanes has been reported, demonstrating efficient conversion of various silane starting materials and high catalyst performance. Molecular modelling of the enzyme-substrate interaction provides a basis for understanding the selectivity of AaeUPO.
ANGEWANDTE CHEMIE-INTERNATIONAL EDITION
(2023)
Article
Chemistry, Medicinal
Anna M. Diaz-Rovira, Helena Martin, Thijs Beuming, Lucia Diaz, Victor Guallar, Soumya S. Ray
Summary: Machine learning-based protein structure prediction algorithms, such as RosettaFold and AlphaFold2, have had a significant impact on the field of structural biology and sparked discussions about their potential role in drug discovery. However, there have been few studies addressing the use of these models in virtual screening, especially with low prior structural information. In this study, we developed an AlphaFold2 version that excludes structural templates with more than 30% sequence identity, and found that using these structures directly may not be ideal for virtual screening campaigns, suggesting the need for post-processing modeling to generate more realistic binding site models.
JOURNAL OF CHEMICAL INFORMATION AND MODELING
(2023)
Article
Chemistry, Physical
Sergi Roda, Henrik Terholsen, Jule Ruth Heike Meyer, Albert Canellas-Sole, Victor Guallar, Uwe Bornscheuer, Masoud Kazemi
Summary: With advances in protein structure predictions, structure-based enzyme engineering is becoming increasingly important. AsiteDesign is a Monte Carlo-based protocol for introducing new catalytic residues in a binding pocket. It was successfully tested in designing alternative catalytic triads and enhancing the hydrolysis of a bulky chiral substrate by Pseudomonas fluorescens esterase.
JOURNAL OF PHYSICAL CHEMISTRY B
(2023)
Article
Biochemistry & Molecular Biology
Laura Fernandez-Lopez, Sergi Roda, Ana Robles-Martin, Ruben Munoz-Tafalla, David Almendral, Manuel Ferrer, Victor Guallar
Summary: Lipases have valuable potential for industrial use, but often require engineering modifications for optimal performance. This study improved the lipase activity by mutating its lid domain and swapping it with another lipase's lid domain, demonstrating the importance of lid domains in determining substrate specificity.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2023)