39 results on '"Atanu Acharya"'
Search Results
2. Influence of the First Chromophore-Forming Residue on Photobleaching and Oxidative Photoconversion of EGFP and EYFP
- Author
-
Tirthendu Sen, Anastasia V. Mamontova, Anastasia V. Titelmayer, Aleksander M. Shakhov, Artyom A. Astafiev, Atanu Acharya, Konstantin A. Lukyanov, Anna I. Krylov, and Alexey M. Bogdanov
- Subjects
fluorescent proteins ,gfp ,quantum mechanics/molecular mechanics (qm/mm) ,atomistic calculations ,photostability ,fluorescence spectroscopy ,light-induced oxidation ,chromophore ,redding ,excited-state lifetime ,Biology (General) ,QH301-705.5 ,Chemistry ,QD1-999 - Abstract
Enhanced green fluorescent protein (EGFP)—one of the most widely applied genetically encoded fluorescent probes—carries the threonine-tyrosine-glycine (TYG) chromophore. EGFP efficiently undergoes green-to-red oxidative photoconversion (“redding”) with electron acceptors. Enhanced yellow fluorescent protein (EYFP), a close EGFP homologue (five amino acid substitutions), has a glycine-tyrosine-glycine (GYG) chromophore and is much less susceptible to redding, requiring halide ions in addition to the oxidants. In this contribution we aim to clarify the role of the first chromophore-forming amino acid in photoinduced behavior of these fluorescent proteins. To that end, we compared photobleaching and redding kinetics of EGFP, EYFP, and their mutants with reciprocally substituted chromophore residues, EGFP-T65G and EYFP-G65T. Measurements showed that T65G mutation significantly increases EGFP photostability and inhibits its excited-state oxidation efficiency. Remarkably, while EYFP-G65T demonstrated highly increased spectral sensitivity to chloride, it is also able to undergo redding chloride-independently. Atomistic calculations reveal that the GYG chromophore has an increased flexibility, which facilitates radiationless relaxation leading to the reduced fluorescence quantum yield in the T65G mutant. The GYG chromophore also has larger oscillator strength as compared to TYG, which leads to a shorter radiative lifetime (i.e., a faster rate of fluorescence). The faster fluorescence rate partially compensates for the loss of quantum efficiency due to radiationless relaxation. The shorter excited-state lifetime of the GYG chromophore is responsible for its increased photostability and resistance to redding. In EYFP and EYFP-G65T, the chromophore is stabilized by π-stacking with Tyr203, which suppresses its twisting motions relative to EGFP.
- Published
- 2019
- Full Text
- View/download PDF
3. Supercomputer-Based Ensemble Docking Drug Discovery Pipeline with Application to Covid-19.
- Author
-
Atanu Acharya, Rupesh Agarwal, Matthew B. Baker, Jérôme Baudry, Debsindhu Bhowmik, Swen Böhm, Kendall G. Byler, Sam Yen-Chi Chen, Leighton Coates, Connor J. Cooper, Omar Demerdash, Isabella Daidone, John D. Eblen, Sally R. Ellingson, Stefano Forli, Jens Glaser, James C. Gumbart, John Gunnels, Oscar R. Hernandez, Stephan Irle, Daniel W. Kneller, Andrey Kovalevsky, Jeffrey M. Larkin, Travis J. Lawrence, Scott LeGrand, Shih-Hsien Liu, Julie C. Mitchell, Gilchan Park, Jerry M. Parks, Anna Pavlova, Loukas Petridis, Duncan Poole, Line Pouchard, Arvind Ramanathan, David M. Rogers, Diogo Santos-Martins, Aaron Scheinberg, Ada Sedova, Yue Shen, Jeremy C. Smith, Micholas Dean Smith, Carlos Soto 0003, Aristides Tsaris, Mathialakan Thavappiragasam, Andreas F. Tillack, Josh Vincent Vermaas, Van Quan Vuong, Junqi Yin, Shinjae Yoo, Mai Zahran, and Laura Zanetti Polzi
- Published
- 2020
- Full Text
- View/download PDF
4. Restoring and Enhancing the Potency of Existing Antibiotics against Drug-Resistant Gram-Negative Bacteria through the Development of Potent Small-Molecule Adjuvants
- Author
-
Bingchen Yu, Manjusha Roy Choudhury, Xiaoxiao Yang, Stéphane L. Benoit, Edroyal Womack, Kristin Van Mouwerik Lyles, Atanu Acharya, Arvind Kumar, Ce Yang, Anna Pavlova, Mengyuan Zhu, Zhengnan Yuan, James C. Gumbart, David W. Boykin, Robert J. Maier, Zehava Eichenbaum, and Binghe Wang
- Subjects
Mice ,Infectious Diseases ,Drug Resistance, Multiple, Bacterial ,Escherichia coli Proteins ,Drug Resistance, Bacterial ,Gram-Negative Bacteria ,Escherichia coli ,Animals ,Adjuvants, Pharmaceutic ,Anti-Bacterial Agents - Abstract
The rapid and persistent emergence of drug-resistant bacteria poses a looming public health crisis. The possible task of developing new sets of antibiotics to replenish the existing ones is daunting to say the least. Searching for adjuvants that restore or even enhance the potency of existing antibiotics against drug-resistant strains of bacteria represents a practical and cost-effective approach. Herein, we describe the discovery of potent adjuvants that extend the antimicrobial spectrum of existing antibiotics and restore their effectiveness toward drug-resistant strains including
- Published
- 2022
5. Many Roles of Carbohydrates: A Computational Spotlight on the Coronavirus S Protein Binding
- Author
-
Suman Maity and Atanu Acharya
- Subjects
Biomaterials ,Biochemistry (medical) ,Biomedical Engineering ,General Chemistry - Published
- 2023
6. Insights into substrate transport and water permeation in the mycobacterial transporter MmpL3
- Author
-
Yupeng Li, Atanu Acharya, Lixinhao Yang, Jinchan Liu, Emad Tajkhorshid, Helen I. Zgurskaya, Mary Jackson, and James C. Gumbart
- Subjects
Biophysics - Published
- 2023
7. Proton transfer activity of the reconstituted
- Author
-
Casey M, Stevens, Svitlana O, Babii, Amitkumar N, Pandya, Wei, Li, Yupeng, Li, Jitender, Mehla, Robyn, Scott, Pooja, Hegde, Pavan K, Prathipati, Atanu, Acharya, Jinchan, Liu, James C, Gumbart, Jeffrey, North, Mary, Jackson, and Helen I, Zgurskaya
- Subjects
Ion Transport ,Bacterial Proteins ,Mycolic Acids ,Lipid Bilayers ,Membrane Transport Proteins ,Corynebacterium ,Protons ,Substrate Specificity - Abstract
Transporters belonging to the Resistance-Nodulation-cell Division (RND) superfamily of proteins such as
- Published
- 2023
8. Proton transfer activity of the reconstituted Mycobacterium tuberculosis MmpL3 is modulated by substrate mimics and inhibitors
- Author
-
Casey M. Stevens, Svitlana O. Babii, Amitkumar N. Pandya, Wei Li, Yupeng Li, Jitender Mehla, Robyn Scott, Pooja Hegde, Pavan K. Prathipati, Atanu Acharya, Jinchan Liu, James C. Gumbart, Jeffrey North, Mary Jackson, and Helen I. Zgurskaya
- Subjects
Multidisciplinary - Abstract
Transporters belonging to the Resistance-Nodulation-cell Division (RND) superfamily of proteins such as Mycobacterium tuberculosis MmpL3 and its analogs are the focus of intense investigations due to their importance in the physiology of Corynebacterium–Mycobacterium–Nocardia species and antimycobacterial drug discovery. These transporters deliver trehalose monomycolates, the precursors of major lipids of the outer membrane, to the periplasm by a proton motive force–dependent mechanism. In this study, we successfully purified, from native membranes, the full-length and the C-terminal truncated M. tuberculosis MmpL3 and Corynebacterium glutamicum CmpL1 proteins and reconstituted them into proteoliposomes. We also generated a series of substrate mimics and inhibitors specific to these transporters, analyzed their activities in the reconstituted proteoliposomes, and carried out molecular dynamics simulations of the model MmpL3 transporter at different pH. We found that all reconstituted proteins facilitate proton translocation across a phospholipid bilayer, but MmpL3 and CmpL1 differ dramatically in their responses to pH and interactions with substrate mimics and indole-2-carboxamide inhibitors. Our results further suggest that some inhibitors abolish the transport activity of MmpL3 and CmpL1 by inhibition of proton translocation.
- Published
- 2022
9. Machine Learning Reveals the Critical Interactions for SARS-CoV-2 Spike Protein Binding to ACE2
- Author
-
Chris Chipot, Zhongyu Mou, Diane L. Lynch, Anna Pavlova, Yui Tik Pang, James C. Gumbart, Atanu Acharya, Zijian Zhang, and Jerry M. Parks
- Subjects
Models, Molecular ,0301 basic medicine ,2019-20 coronavirus outbreak ,Letter ,Coronavirus disease 2019 (COVID-19) ,Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) ,Biophysics ,Molecular Dynamics Simulation ,Machine learning ,computer.software_genre ,Machine Learning ,03 medical and health sciences ,Molecular dynamics ,0302 clinical medicine ,Humans ,General Materials Science ,Physical and Theoretical Chemistry ,Binding site ,Binding Sites ,business.industry ,Chemistry ,Spike Protein ,030104 developmental biology ,Spike Glycoprotein, Coronavirus ,Free energies ,Angiotensin-Converting Enzyme 2 ,Artificial intelligence ,business ,computer ,hormones, hormone substitutes, and hormone antagonists ,030217 neurology & neurosurgery - Abstract
SARS-CoV and SARS-CoV-2 bind to the human ACE2 receptor in practically identical conformations, although several residues of the receptor-binding domain (RBD) differ between them. Herein, we have used molecular dynamics (MD) simulations, machine learning (ML), and free-energy perturbation (FEP) calculations to elucidate the differences in binding by the two viruses. Although only subtle differences were observed from the initial MD simulations of the two RBD–ACE2 complexes, ML identified the individual residues with the most distinctive ACE2 interactions, many of which have been highlighted in previous experimental studies. FEP calculations quantified the corresponding differences in binding free energies to ACE2, and examination of MD trajectories provided structural explanations for these differences. Lastly, the energetics of emerging SARS-CoV-2 mutations were studied, showing that the affinity of the RBD for ACE2 is increased by N501Y and E484K mutations but is slightly decreased by K417N.
- Published
- 2021
10. A 300-fold conductivity increase in microbial cytochrome nanowires due to temperature-induced restructuring of hydrogen bonding networks
- Author
-
Peter J. Dahl, Sophia M. Yi, Yangqi Gu, Atanu Acharya, Catharine Shipps, Jens Neu, J. Patrick O’Brien, Uriel N. Morzan, Subhajyoti Chaudhuri, Matthew J. Guberman-Pfeffer, Dennis Vu, Sibel Ebru Yalcin, Victor S. Batista, and Nikhil S. Malvankar
- Subjects
Multidisciplinary - Abstract
Although proteins are considered as nonconductors that transfer electrons only up to 1 to 2 nanometers via tunneling, Geobacter sulfurreducens transports respiratory electrons over micrometers, to insoluble acceptors or syntrophic partner cells, via nanowires composed of polymerized cytochrome OmcS. However, the mechanism enabling this long-range conduction is unclear. Here, we demonstrate that individual nanowires exhibit theoretically predicted hopping conductance, at rate (>10 10 s −1 ) comparable to synthetic molecular wires, with negligible carrier loss over micrometers. Unexpectedly, nanowires show a 300-fold increase in their intrinsic conductance upon cooling, which vanishes upon deuteration. Computations show that cooling causes a massive rearrangement of hydrogen bonding networks in nanowires. Cooling makes hemes more planar, as revealed by Raman spectroscopy and simulations, and lowers their reduction potential. We find that the protein surrounding the hemes acts as a temperature-sensitive switch that controls charge transport by sensing environmental perturbations. Rational engineering of heme environments could enable systematic tuning of extracellular respiration.
- Published
- 2022
11. SARS-CoV-2 spike opening dynamics and energetics reveal the individual roles of glycans and their collective impact
- Author
-
James C. Gumbart, Diane L. Lynch, Anna Pavlova, Yui Tik Pang, and Atanu Acharya
- Subjects
Glycan ,Glycosylation ,Stereochemistry ,Biophysics ,Medicine (miscellaneous) ,Protomer ,Peptidyl-Dipeptidase A ,General Biochemistry, Genetics and Molecular Biology ,Epitope ,chemistry.chemical_compound ,Molecular dynamics ,Epitopes ,Viral envelope ,Polysaccharides ,Humans ,chemistry.chemical_classification ,biology ,Chemistry ,SARS-CoV-2 ,COVID-19 ,Spike Glycoprotein, Coronavirus ,biology.protein ,Angiotensin-Converting Enzyme 2 ,Umbrella sampling ,General Agricultural and Biological Sciences ,Glycoprotein - Abstract
The trimeric spike (S) glycoprotein, which protrudes from the SARS-CoV-2 viral envelope, is responsible for binding to human ACE2 receptors. The binding process is initiated when the receptor binding domain (RBD) of at least one protomer switches from a "down" (closed) to an "up" (open) state. Here, we used molecular dynamics simulations and two-dimensional replica exchange umbrella sampling calculations to investigate the transition between the two S-protein conformations with and without glycosylation. We show that the glycosylated spike has a higher barrier to opening than the non-glycosylated one with comparable populations of the down and up states. In contrast, we observed that the up conformation is favored without glycans. Analysis of the S-protein opening pathway reveals that glycans at N165 and N122 interfere with hydrogen bonds between the RBD and the N-terminal domain in the up state. We also identify roles for glycans at N165 and N343 in stabilizing the down and up states. Finally we estimate how epitope exposure for several known antibodies changes along the opening path. We find that the epitope of the BD-368-2 antibody remains exposed irrespective of the S-protein conformation, explaining the high efficacy of this antibody. Graphical TOC Entry O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=81 SRC="FIGDIR/small/456168v1_ufig1.gif" ALT="Figure 1"> View larger version (28K): org.highwire.dtl.DTLVardef@1fcc0a5org.highwire.dtl.DTLVardef@cb97cforg.highwire.dtl.DTLVardef@5bbe6corg.highwire.dtl.DTLVardef@132ca97_HPS_FORMAT_FIGEXP M_FIG C_FIG
- Published
- 2023
12. Resolving the hydride transfer pathway in oxidative conversion of proline to pyrrole
- Author
-
Dongqi Yi, Atanu Acharya, Anna Pavlova, James C. Gumbart, and Vinayak Agarwal
- Subjects
Proline ,Protein Conformation ,Stereochemistry ,Bone Morphogenetic Protein 3 ,Molecular Dynamics Simulation ,Biochemistry ,chemistry.chemical_compound ,Deprotonation ,Catalytic Domain ,Flavins ,Side chain ,Molecule ,Pyrroles ,Pyrrole ,Molecular Structure ,biology ,Hydrogen bond ,Hydride ,Active site ,Hydrogen Bonding ,Tautomer ,chemistry ,Biocatalysis ,biology.protein ,Quantum Theory ,Carrier Proteins ,Oxidoreductases ,Oxidation-Reduction - Abstract
Thiotemplated pyrrole is a prevailing intermediate in the synthesis of numerous natural products where the pyrrole is tethered to a carrier protein (CP). Biosynthesis of the pyrrole requires oxidation of an L-proline side chain. Herein, we investigated the biocatalytic mechanism of proline-to-pyrrole synthesis using the recently reported (Thapa et al., Biochemistry, 2019, 58, 918) structure of a Type II non-ribosomal protein synthetase (NRPS) Bmp3-Bmp1 (Oxidase-CP) complex. The substrate (L-proline side chain) is attached to the Bmp1(CP) and the catalytic site is located inside the flavin-dependent oxidase (Bmp3). Interestingly, the FAD molecule is free (unbound) within the Bmp3 catalytic site. We show that the FAD isoalloxazine ring is stabilized in the catalytic site of Bmp3 by strong hydrogen bonding with Asn123, Ile125, Ser126, and Thr158. The stability of the dimeric Bmp3 system including one FAD molecule in our simulation suggests that the tetrameric Bmp3 assembly, as found in the crystal structure, is not functionally important. After the initial deprotonation followed by an enamine-imine tautomerization, oxidation of either the C2-C3 bond or the C2-N1 bond, through a hydride transfer (either from C3 or N1), is required for the pyrrole synthesis. Using molecular dynamics simulations, quantum mechanics/molecular mechanics simulations, and electronic structure calculations, we conclude that the hydride transfer is more likely to occur from C3 than N1. Additionally, we demonstrated the elasticity in the oxidase active site through enzymatic synthesis of proline derivatives.
- Published
- 2021
13. ACE2 glycans preferentially interact with SARS-CoV-2 over SARS-CoV
- Author
-
James C. Gumbart, Diane L. Lynch, Anna Pavlova, Yui Tik Pang, and Atanu Acharya
- Subjects
2019-20 coronavirus outbreak ,Glycan ,Glycosylation ,Coronavirus disease 2019 (COVID-19) ,viruses ,Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) ,Protein domain ,Plasma protein binding ,Molecular Dynamics Simulation ,Catalysis ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Protein Domains ,Polysaccharides ,Materials Chemistry ,Humans ,skin and connective tissue diseases ,030304 developmental biology ,0303 health sciences ,biology ,Chemistry ,SARS-CoV-2 ,fungi ,Metals and Alloys ,General Chemistry ,Surfaces, Coatings and Films ,Electronic, Optical and Magnetic Materials ,Cell biology ,body regions ,Severe acute respiratory syndrome-related coronavirus ,Spike Glycoprotein, Coronavirus ,Ceramics and Composites ,biology.protein ,Angiotensin-Converting Enzyme 2 ,hormones, hormone substitutes, and hormone antagonists ,030217 neurology & neurosurgery ,Protein Binding - Abstract
We report a distinct difference in the interactions of the glycans of the host-cell receptor, ACE2, with SARS-CoV-2 and SARS-CoV S-protein receptor-binding domains (RBDs). Our analysis demonstrates that the ACE2 glycan at N322 enhances interactions with the SARS-CoV-2 RBD while the ACE2 glycan at N90 may offer protection against infections of both coronaviruses depending on its composition. The interactions of the ACE2 glycan at N322 with SARS-CoV RBD are blocked by the presence of the RBD glycan at N357 of the SARS-CoV RBD. The absence of this glycosylation site on SARS-CoV-2 RBD may enhance its binding with ACE2.
- Published
- 2021
14. Gatekeeping Ketosynthases Dictate Initiation of Assembly Line Biosynthesis of Pyrrolic Polyketides
- Author
-
Will R. Gutekunst, Dongqi Yi, James C. Gumbart, Vinayak Agarwal, and Atanu Acharya
- Subjects
Substrate Specificities ,Biological Products ,biology ,Chemistry ,Stereochemistry ,High selectivity ,Active site ,Rational engineering ,Context (language use) ,General Chemistry ,010402 general chemistry ,01 natural sciences ,Biochemistry ,Catalysis ,0104 chemical sciences ,Polyketide ,chemistry.chemical_compound ,Colloid and Surface Chemistry ,Biosynthesis ,Polyketides ,biology.protein ,Assembly line ,Polyketide Synthases - Abstract
Assembly line biosynthesis of polyketide natural products involves checkpoints where identities of thiotemplated intermediates are verified before polyketide extension reactions are allowed to proceed. Determining what these checkpoints are and how they operate is critical for reprogramming polyketide assembly lines. Here we demonstrate that ketosynthase (KS) domains can perform this gatekeeping role. By comparing the substrate specificities for polyketide synthases that extend pyrrolyl and halogenated pyrrolyl substrates, we find that KS domains that need to differentiate between these two substrates exercise high selectivity. We additionally find that amino acid residues in the KS active site facilitate this selectivity and that these residues are amenable to rational engineering. On the other hand, KS domains that do not need to make selectivity decisions in their native physiological context are substrate-promiscuous. We also provide evidence that delivery of substrates to polyketide synthases by non-native carrier proteins is accompanied by reduced biosynthetic efficiency.
- Published
- 2021
15. ACE2 glycans preferentially interact with the RBD of SARS-CoV-2 over SARS-CoV
- Author
-
James C. Gumbart, Diane L. Lynch, Anna Pavlova, Atanu Acharya, and Yui Tik Pang
- Subjects
Glycan ,2019-20 coronavirus outbreak ,Glycosylation ,Coronavirus disease 2019 (COVID-19) ,viruses ,Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) ,fungi ,Biology ,Virology ,body regions ,chemistry.chemical_compound ,chemistry ,biology.protein ,skin and connective tissue diseases ,hormones, hormone substitutes, and hormone antagonists - Abstract
We report a distinct difference in the interactions of the glycans of the host-cell receptor, ACE2, with SARS-CoV-2 and SARS-CoV S-protein receptor-binding domains (RBDs). Our analysis demonstrates that the ACE2 glycan at N90 may offer protection against infections of both coronaviruses, while the ACE2 glycan at N322 enhances interactions with the SARS-CoV-2 RBD. The interactions of the ACE2 glycan at N322 with SARS-CoV RBD are blocked by the presence of the RBD glycan at N357 of the SARS-CoV RBD. The absence of this glycosylation site on SARS-CoV-2 RBD may enhance its binding with ACE2.
- Published
- 2021
16. Regioselective Ultrafast Photoinduced Electron Transfer from Naphthols to Halocarbon Solvents
- Author
-
Subhajyoti Chaudhuri, Victor S. Batista, Atanu Acharya, and Erik T. J. Nibbering
- Subjects
Chloroform ,010304 chemical physics ,Chemistry ,Regioselectivity ,Halocarbon ,Electronic structure ,010402 general chemistry ,Photochemistry ,01 natural sciences ,Photoinduced electron transfer ,0104 chemical sciences ,chemistry.chemical_compound ,Electron transfer ,Excited state ,0103 physical sciences ,Molecule ,General Materials Science ,Physical and Theoretical Chemistry - Abstract
Excited state decay of 2-naphthol (2N) in halocarbon solvents has been observed to be significantly slower when compared to that of 1-naphthol (1N). In this study, we provide new physical insights behind this observation by exploring the regioselective electron transfer (ET) mechanism from photoexcited 1N and 2N to halocarbon solvents at a detailed molecular level. Using state-of-the-art electronic structure calculations, we explore several configurations of naphthol-chloroform complexes and find that the proximity of the electron-accepting chloroform molecule to the electron-rich -OH group of the naphthol is the dominant factor affecting electron transfer rates. The origin of significantly slower electron transfer rates for 2N is traced back to the notably smaller electronic coupling when the electron-accepting chloroform molecule is on top of the aromatic ring distal to the -OH group. Our findings suggest that regioselective photoinduced electron transfer could thus be exploited to control electron transfer in substituted acenes tailored for specific applications.
- Published
- 2019
17. Critical interactions for SARS-CoV-2 spike protein binding to ACE2 identified by machine learning
- Author
-
Zhongyu Mou, James C. Gumbart, Diane L. Lynch, Anna Pavlova, Jerry M. Parks, Atanu Acharya, Chris Chipot, Zijian Zhang, and Yui Tik Pang
- Subjects
2019-20 coronavirus outbreak ,Coronavirus disease 2019 (COVID-19) ,Chemistry ,business.industry ,Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) ,Spike Protein ,Machine learning ,computer.software_genre ,Free energy perturbation ,Molecular dynamics ,Free energies ,Artificial intelligence ,business ,computer ,hormones, hormone substitutes, and hormone antagonists - Abstract
Both SARS-CoV and SARS-CoV-2 bind to the human ACE2 receptor. Based on high-resolution structures, the two viruses bind in practically identical conformations, although several residues of the receptor-binding domain (RBD) differ between them. Here we have used molecular dynamics (MD) simulations, machine learning (ML), and free energy perturbation (FEP) calculations to elucidate the differences in RBD binding by the two viruses. Although only subtle differences were observed from the initial MD simulations of the two RBD-ACE2 complexes, ML identified the individual residues with the most distinctive ACE2 interactions, many of which have been highlighted in previous experimental studies. FEP calculations quantified the corresponding differences in binding free energies to ACE2, and examination of MD trajectories provided structural explanations for these differences. Lastly, the energetics of emerging SARS-CoV-2 mutations were studied, showing that the affinity of the RBD for ACE2 is increased by N501Y and E484K mutations but is slightly decreased by K417N.
- Published
- 2021
18. Inhibitor binding influences the protonation states of histidines in SARS-CoV-2 main protease
- Author
-
Micholas Dean Smith, Jerry M. Parks, Daniel W. Kneller, Jeremy C. Smith, Andrei Golosov, Leighton Coates, Isabella Daidone, Camilo Velez-Vega, Atanu Acharya, Chris Chipot, Callum J. Dickson, Diane L. Lynch, Anna Pavlova, Yui Tik Pang, José S. Duca, James C. Gumbart, Josh V. Vermaas, Andrey Kovalevsky, and Laura Zanetti-Polzi
- Subjects
Peptidomimetic ,Stereochemistry ,medicine.medical_treatment ,viruses ,Protonation ,010402 general chemistry ,Cleavage (embryo) ,01 natural sciences ,Article ,03 medical and health sciences ,0103 physical sciences ,medicine ,Binding site ,Histidine ,030304 developmental biology ,0303 health sciences ,Protease ,010304 chemical physics ,010405 organic chemistry ,Chemistry ,Hydrogen bond ,virus diseases ,General Chemistry ,Cysteine protease ,0104 chemical sciences - Abstract
The main protease (Mpro) of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is an attractive target for antiviral therapeutics. Recently, many high-resolution apo and inhibitor-bound structures of Mpro, a cysteine protease, have been determined, facilitating structure-based drug design. Mpro plays a central role in the viral life cycle by catalyzing the cleavage of SARS-CoV-2 polyproteins. In addition to the catalytic dyad His41-Cys145, Mpro contains multiple histidines including His163, His164, and His172. The protonation states of these histidines and the catalytic nu-cleophile Cys145 have been debated in previous studies of SARS-CoV Mpro, but have yet to be investigated for SARS-CoV-2. In this work we have used molecular dynamics simulations to determine the structural stability of SARS-CoV-2 Mpro as a function of the protonation assignments for these residues. We simulated both the apo and inhibitor-bound enzyme and found that the conformational stability of the binding site, bound inhibitors, and the hydrogen bond networks of Mpro are highly sensitive to these assignments. Additionally, the two inhibitors studied, the peptidomimetic N3 and an α-ketoamide, display distinct His41/His164 protonation-state-dependent stabilities. While the apo and the N3-bound systems favored Nδ (HD) and Nϵ (HE) protonation of His41 and His164, respectively, the α-ketoamide was not stably bound in this state. Our results illustrate the importance of using appropriate histidine protonation states to accurately model the structure and dynamics of SARS-CoV-2 Mpro in both the apo and inhibitor-bound states, a necessary prerequisite for drug-design efforts.
- Published
- 2021
19. Electric field stimulates production of highly conductive microbial OmcZ nanowires
- Author
-
Vishok Srikanth, Atanu Acharya, Nikhil S. Malvankar, Sophia M. Yi, Yangqi Gu, Tamas Varga, Sibel Ebru Yalcin, J. Patrick O'Brien, Winston Huynh, Krystle Reiss, Subhajyoti Chaudhuri, Ruchi Jain, Dennis Vu, Peter Dahl, and Victor S. Batista
- Subjects
0303 health sciences ,Materials science ,biology ,Cytochrome ,Nanowires ,030302 biochemistry & molecular biology ,Nanowire ,Electric Conductivity ,Nanotechnology ,Cell Biology ,Conductivity ,biology.organism_classification ,Electric Stimulation ,Electrophysiological Phenomena ,03 medical and health sciences ,Protein structure ,Bacterial Proteins ,Electrical resistivity and conductivity ,Electric field ,biology.protein ,Geobacter ,Molecular Biology ,Geobacter sulfurreducens ,Electrical conductor ,030304 developmental biology - Abstract
Multifunctional living materials are attractive due to their powerful ability to self-repair and replicate. However, most natural materials lack electronic functionality. Here we show that an electric field, applied to electricity-producing Geobacter sulfurreducens biofilms, stimulates production of cytochrome OmcZ nanowires with 1,000-fold higher conductivity (30 S cm−1) and threefold higher stiffness (1.5 GPa) than the cytochrome OmcS nanowires that are important in natural environments. Using chemical imaging-based multimodal nanospectroscopy, we correlate protein structure with function and observe pH-induced conformational switching to β-sheets in individual nanowires, which increases their stiffness and conductivity by 100-fold due to enhanced π-stacking of heme groups; this was further confirmed by computational modeling and bulk spectroscopic studies. These nanowires can transduce mechanical and chemical stimuli into electrical signals to perform sensing, synthesis and energy production. These findings of biologically produced, highly conductive protein nanowires may help to guide the development of seamless, bidirectional interfaces between biological and electronic systems. Application of an electrical field to Geobacter sulfurreducens biofilms stimulates production of OmcZ nanowires, which undergo a pH-induced conformational switch that causes increased stiffness and conductivity due to enhanced heme group π-stacking.
- Published
- 2020
20. Supercomputer-Based Ensemble Docking Drug Discovery Pipeline with Application to Covid-19
- Author
-
Mathialakan Thavappiragasam, Gilchan Park, Kendall G. Byler, Leighton Coates, Laura Zanetti-Polzi, Jeffrey M. Larkin, Junqi Yin, John A. Gunnels, Omar Demerdash, Loukas Petridis, Ada Sedova, Carlos Soto, Aaron Scheinberg, Mai Zahran, Scott LeGrand, Jens Glaser, Jerome Baudry, Stephan Irle, Samuel Yen-Chi Chen, Andrey Kovalevsky, Isabella Daidone, Julie C. Mitchell, Arvind Ramanathan, Connor J. Cooper, Duncan Poole, V. Q. Vuong, Diogo Santos-Martins, David M. Rogers, Shinjae Yoo, Y. Shen, Oscar Hernandez, A. Tsaris, Swen Boehm, Debsindhu Bhowmik, Travis J Lawrence, Daniel W. Kneller, Shih-Hsien Liu, Jeremy C. Smith, Line Pouchard, Matthew B. Baker, Stefano Forli, Sally R. Ellingson, Anna Pavlova, Rupesh Agarwal, Micholas Dean Smith, Atanu Acharya, James C. Gumbart, Andreas F. Tillack, John D. Eblen, Josh V. Vermaas, and Jerry M. Parks
- Subjects
Enhanced sampling ,Computer science ,Protein Conformation ,General Chemical Engineering ,Drug Evaluation, Preclinical ,Viral Nonstructural Proteins ,Replica exchange ,01 natural sciences ,Molecular Docking Simulation ,Molecular dynamics ,010304 chemical physics ,Drug discovery ,AutoDock ,Supercomputer ,Supercomputers ,Preclinical ,Spike Glycoprotein ,Computer Science Applications ,Spike Glycoprotein, Coronavirus ,Coronavirus disease 2019 (COVID-19) ,Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) ,Chemical ,Library and Information Sciences ,Antiviral Agents ,Article ,Autodock vina ,Computational science ,Databases ,Structure-Activity Relationship ,Artificial Intelligence ,0103 physical sciences ,Humans ,Computer Simulation ,Binding Sites ,SARS-CoV-2 ,COVID-19 ,Proteins ,General Chemistry ,0104 chemical sciences ,COVID-19 Drug Treatment ,Coronavirus ,010404 medicinal & biomolecular chemistry ,Massively parallel supercomputing ,Docking (molecular) ,Drug Design ,Drug Evaluation ,Databases, Chemical - Abstract
We present a supercomputer-driven pipeline for in silico drug discovery using enhanced sampling molecular dynamics (MD) and ensemble docking. Ensemble docking makes use of MD results by docking compound databases into representative protein binding-site conformations, thus taking into account the dynamic properties of the binding sites. We also describe preliminary results obtained for 24 systems involving eight proteins of the proteome of SARS-CoV-2. The MD involves temperature replica exchange enhanced sampling, making use of massively parallel supercomputing to quickly sample the configurational space of protein drug targets. Using the Summit supercomputer at the Oak Ridge National Laboratory, more than 1 ms of enhanced sampling MD can be generated per day. We have ensemble docked repurposing databases to 10 configurations of each of the 24 SARS-CoV-2 systems using AutoDock Vina. Comparison to experiment demonstrates remarkably high hit rates for the top scoring tranches of compounds identified by our ensemble approach. We also demonstrate that, using Autodock-GPU on Summit, it is possible to perform exhaustive docking of one billion compounds in under 24 h. Finally, we discuss preliminary results and planned improvements to the pipeline, including the use of quantum mechanical (QM), machine learning, and artificial intelligence (AI) methods to cluster MD trajectories and rescore docking poses.
- Published
- 2020
- Full Text
- View/download PDF
21. Allosteric Motions of the CRISPR-Cas9 HNH Nuclease Probed by NMR and Molecular Dynamics
- Author
-
Victor S. Batista, Jocelyn C. Newton, Gerwald Jogl, Kyle W. East, Uriel N. Morzan, George P. Lisi, Erin Skeens, Atanu Acharya, Yogesh B. Narkhede, and Giulia Palermo
- Subjects
Allosteric regulation ,Computational biology ,Molecular Dynamics Simulation ,010402 general chemistry ,01 natural sciences ,Biochemistry ,DNA-binding protein ,Catalysis ,Article ,chemistry.chemical_compound ,Molecular dynamics ,Endonuclease ,Colloid and Surface Chemistry ,Allosteric Regulation ,CRISPR ,Nuclear Magnetic Resonance, Biomolecular ,Nuclease ,Deoxyribonucleases ,biology ,Cas9 ,General Chemistry ,0104 chemical sciences ,chemistry ,biology.protein ,CRISPR-Cas Systems ,DNA - Abstract
CRISPR-Cas9 is a widely employed genome-editing tool with functionality reliant on the ability of the Cas9 endonuclease to introduce site-specific breaks in double-stranded DNA. In this system, an intriguing allosteric communication has been suggested to control its DNA cleavage activity through flexibility of the catalytic HNH domain. Here, solution NMR experiments and a novel Gaussian-accelerated molecular dynamics (GaMD) simulation method are used to capture the structural and dynamic determinants of allosteric signaling within the HNH domain. We reveal the existence of a millisecond time scale dynamic pathway that spans HNH from the region interfacing the adjacent RuvC nuclease and propagates up to the DNA recognition lobe in full-length CRISPR-Cas9. These findings reveal a potential route of signal transduction within the CRISPR-Cas9 HNH nuclease, advancing our understanding of the allosteric pathway of activation. Further, considering the role of allosteric signaling in the specificity of CRISPR-Cas9, this work poses the mechanistic basis for novel engineering efforts aimed at improving its genome-editing capability.
- Published
- 2019
22. The Effect of (-)-Epigallocatechin-3-Gallate on the Amyloid-β Secondary Structure
- Author
-
Victor S. Batista, Klaus Gerwert, Andreas Nabers, Julia Stockmann, James C. Gumbart, Atanu Acharya, Till Rudack, and Léon Beyer
- Subjects
0303 health sciences ,Conformational change ,Amyloid ,Amyloid beta-Peptides ,Chemistry ,Biophysics ,food and beverages ,Articles ,Fibril ,Oligomer ,Catechin ,Peptide Fragments ,Protein Structure, Secondary ,03 medical and health sciences ,Molecular dynamics ,chemistry.chemical_compound ,0302 clinical medicine ,Docking (molecular) ,Protein secondary structure ,030217 neurology & neurosurgery ,030304 developmental biology ,Macromolecule - Abstract
Amyloid-β (Aβ) is a macromolecular structure of great interest because its misfolding and aggregation, along with changes in the secondary structure, have been correlated with its toxicity in various neurodegenerative diseases. Small drug-like molecules can modulate the amyloid secondary structure and therefore have raised significant interest in applications to active and passive therapies targeting amyloids. In this study, we investigate the interactions of epigallocatechin-3-gallate (EGCG), found in green tea, with Aβ polypeptides, using a combination of in vitro immuno-infrared sensor measurements, docking, molecular dynamics simulations, and ab initio calculations. We find that the interactions of EGCG are dominated by only a few residues in the fibrils, including hydrophobic π-π interactions with aromatic rings of side chains and hydrophilic interactions with the backbone of Aβ, as confirmed by extended (1-μs-long) molecular dynamics simulations. Immuno-infrared sensor data are consistent with degradation of Aβ fibril induced by EGCG and inhibition of Aβ fibril and oligomer formation, as manifested by the recovery of the amide-I band of monomeric Aβ, which is red-shifted by 26 cm−1 when compared to the amide-I band of the fibrillar form. The shift is rationalized by computations of the infrared spectra of Aβ42 model structures, suggesting that the conformational change involves interchain hydrogen bonds in the amyloid fibrils that are broken upon binding of EGCG.
- Published
- 2019
23. Influence of the First Chromophore-Forming Residue on Photobleaching and Oxidative Photoconversion of EGFP and EYFP
- Author
-
Konstantin A. Lukyanov, A. M. Shakhov, Artyom A. Astafiev, Atanu Acharya, Anastasia V. Mamontova, Anastasia V. Titelmayer, Tirthendu Sen, Anna I. Krylov, and Alexey M. Bogdanov
- Subjects
0301 basic medicine ,Yellow fluorescent protein ,redding ,Amino Acid Motifs ,Quantum yield ,photostability ,01 natural sciences ,Green fluorescent protein ,lcsh:Chemistry ,lcsh:QH301-705.5 ,Spectroscopy ,chemistry.chemical_classification ,Photobleaching ,biology ,Chemistry ,Absorption, Radiation ,General Medicine ,Electron acceptor ,fluorescence spectroscopy ,Fluorescence ,Computer Science Applications ,atomistic calculations ,excited-state lifetime ,Oxidation-Reduction ,Fluorescence Recovery After Photobleaching ,Ultraviolet Rays ,fluorescent proteins ,Green Fluorescent Proteins ,Mutation, Missense ,010402 general chemistry ,Catalysis ,Fluorescence spectroscopy ,Article ,Inorganic Chemistry ,03 medical and health sciences ,Escherichia coli ,chromophore ,quantum mechanics/molecular mechanics (qm/mm) ,Physical and Theoretical Chemistry ,Molecular Biology ,light-induced oxidation ,Organic Chemistry ,fungi ,Chromophore ,gfp ,0104 chemical sciences ,030104 developmental biology ,lcsh:Biology (General) ,lcsh:QD1-999 ,Biophysics ,biology.protein - Abstract
Enhanced green fluorescent protein (EGFP)&mdash, one of the most widely applied genetically encoded fluorescent probes&mdash, carries the threonine-tyrosine-glycine (TYG) chromophore. EGFP efficiently undergoes green-to-red oxidative photoconversion (&ldquo, redding&rdquo, ) with electron acceptors. Enhanced yellow fluorescent protein (EYFP), a close EGFP homologue (five amino acid substitutions), has a glycine-tyrosine-glycine (GYG) chromophore and is much less susceptible to redding, requiring halide ions in addition to the oxidants. In this contribution we aim to clarify the role of the first chromophore-forming amino acid in photoinduced behavior of these fluorescent proteins. To that end, we compared photobleaching and redding kinetics of EGFP, EYFP, and their mutants with reciprocally substituted chromophore residues, EGFP-T65G and EYFP-G65T. Measurements showed that T65G mutation significantly increases EGFP photostability and inhibits its excited-state oxidation efficiency. Remarkably, while EYFP-G65T demonstrated highly increased spectral sensitivity to chloride, it is also able to undergo redding chloride-independently. Atomistic calculations reveal that the GYG chromophore has an increased flexibility, which facilitates radiationless relaxation leading to the reduced fluorescence quantum yield in the T65G mutant. The GYG chromophore also has larger oscillator strength as compared to TYG, which leads to a shorter radiative lifetime (i.e., a faster rate of fluorescence). The faster fluorescence rate partially compensates for the loss of quantum efficiency due to radiationless relaxation. The shorter excited-state lifetime of the GYG chromophore is responsible for its increased photostability and resistance to redding. In EYFP and EYFP-G65T, the chromophore is stabilized by &pi, stacking with Tyr203, which suppresses its twisting motions relative to EGFP.
- Published
- 2019
24. Inward-facing glycine residues create sharp turns in β-barrel membrane proteins
- Author
-
Marcella Orwick Rydmark, James C. Gumbart, David Ryoo, Dirk Linke, Zijian Zhang, Curtis Balusek, and Atanu Acharya
- Subjects
Glycine ,Biophysics ,Molecular Dynamics Simulation ,medicine.disease_cause ,01 natural sciences ,Biochemistry ,Article ,Flattening ,03 medical and health sciences ,Protein Domains ,0103 physical sciences ,medicine ,Escherichia coli ,030304 developmental biology ,Alanine ,chemistry.chemical_classification ,0303 health sciences ,010304 chemical physics ,Chemistry ,Escherichia coli Proteins ,Cell Biology ,Amino acid ,Cross section (geometry) ,Barrel ,Membrane protein ,Protein Conformation, beta-Strand ,Bacterial Outer Membrane Proteins - Abstract
The transmembrane region of outer-membrane proteins (OMPs) of Gram-negative bacteria are almost exclusively β-barrels composed of between 8 and 26 β-strands. To explore the relationship between β-barrel size and shape, we modeled and simulated engineered variants of the Escherichia coli protein OmpX with 8, 10, 12, 14, and 16 β-strands. We found that while smaller barrels maintained a roughly circular shape, the 16-stranded variant developed a flattened cross section. This flat cross section impeded its ability to conduct ions, in agreement with previous experimental observations. Flattening was determined to arise from the presence of inward-facing glycines at sharp turns in the β-barrel. An analysis of all simulations revealed that glycines, on average, make significantly smaller angles with residues on neighboring strands than all other amino acids, including alanine, and create sharp turns in β-barrel cross sections. This observation was generalized to 119 unique structurally resolved OMPs. We also found that the fraction of glycines in β-barrels decreases as the strand number increases, suggesting an evolutionary role for the addition or removal of glycine in OMP sequences.
- Published
- 2021
25. Energetics of Opening for the Glycosylated and Unglycosylated Forms of the SARS-CoV-2 S-Protein Trimer
- Author
-
Diane L. Lynch, Yui Tik Pang, James C. Gumbart, and Atanu Acharya
- Subjects
2019-20 coronavirus outbreak ,Coronavirus disease 2019 (COVID-19) ,Chemistry ,Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) ,Protein trimer ,Energetics ,Biophysics ,Virology ,Article - Published
- 2021
26. Allosteric Motions of the CRISPR-Cas9 HNH Nuclease Probed by NMR and Molecular Dynamics
- Author
-
Atanu Acharya, Victor S. Batista, George P. Lisi, Erin Skeens, Jocelyn C. Newton, Giulia Palermo, Gerwald Jogl, Uriel N. Morzan, and Kyle W. East
- Subjects
Molecular dynamics ,Nuclease ,Endonuclease ,chemistry.chemical_compound ,Genome editing ,biology ,Chemistry ,Cas9 ,Stereochemistry ,Allosteric regulation ,biology.protein ,CRISPR ,DNA - Abstract
CRISPR-Cas9 is a widely employed genome-editing tool with functionality reliant on the ability of the Cas9 endonuclease to introduce site-specific breaks in double-stranded DNA. In this system, an intriguing allosteric communication has been suggested to control its DNA cleavage activity through flexibility of the catalytic HNH domain. Here, solution NMR experiments and a novel Gaussian accelerated Molecular Dynamics (GaMD) simulations method - flanked by mixed machine learning and structure-based prediction of NMR chemical shifts - are used to capture the structural and dynamic determinants of allosteric signaling within the HNH domain. We reveal the existence of a millisecond timescale dynamic pathway that spans HNH from the region interfacing the adjacent RuvC nuclease and propagates up to the DNA recognition lobe in the full-length CRISPR-Cas9. These findings reveal a potential route of signal transduction within the CRISPR-Cas9 HNH nuclease, advancing our understanding of the allosteric pathway of activation. Further, considering the role of allosteric signaling in the specificity of CRISPR-Cas9, this work poses the mechanistic basis for novel engineering efforts aimed at improving its genome editing capability.nnnnO_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=117 SRC="FIGDIR/small/660613v1_ufig1.gif" ALT="Figure 1">nView larger version (64K):norg.highwire.dtl.DTLVardef@1359ddaorg.highwire.dtl.DTLVardef@10e8304org.highwire.dtl.DTLVardef@1bbb285org.highwire.dtl.DTLVardef@1c53cb3_HPS_FORMAT_FIGEXP M_FIG C_FIG
- Published
- 2019
- Full Text
- View/download PDF
27. Distinct Differences in the Interactions of Receptor Binding Domains of SARS-CoV-2 and SARS-CoV with Human ACE2
- Author
-
James C. Gumbart, Anna Pavlova, Atanu Acharya, and Christophe Chipot
- Subjects
2019-20 coronavirus outbreak ,Coronavirus disease 2019 (COVID-19) ,Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) ,Biophysics ,Biology ,Virology ,Article - Published
- 2021
28. Molecular Insights into the Transport of LPS by the Lpt Machinery in Gram-Negative Bacteria
- Author
-
Jinchan Liu, Yupeng Li, Atanu Acharya, and James C. Gumbart
- Subjects
Gram-negative bacteria ,biology ,Chemistry ,Biophysics ,biology.organism_classification ,Microbiology - Published
- 2021
29. Extension of the Effective Fragment Potential Method to Macromolecules
- Author
-
Lyudmila V. Slipchenko, Yihan Shao, Pradeep Kumar Gurunathan, Atanu Acharya, Dmytro Kosenkov, Debashree Ghosh, Anna I. Krylov, and Ilya Kaliman
- Subjects
Models, Molecular ,Green Fluorescent Proteins ,010402 general chemistry ,01 natural sciences ,Force field (chemistry) ,Polarizability ,Ionization ,0103 physical sciences ,Hydroxybenzoates ,Materials Chemistry ,Non-covalent interactions ,Molecule ,Physical and Theoretical Chemistry ,chemistry.chemical_classification ,010304 chemical physics ,Chemistry ,Water ,Potential method ,0104 chemical sciences ,Surfaces, Coatings and Films ,Luminescent Proteins ,Chemical physics ,Quantum Theory ,Muramidase ,Protons ,Atomic physics ,Excitation ,Macromolecule - Abstract
The effective fragment potential (EFP) approach, which can be described as a nonempirical polarizable force field, affords an accurate first-principles treatment of noncovalent interactions in extended systems. EFP can also describe the effect of the environment on the electronic properties (e.g., electronic excitation energies and ionization and electron-attachment energies) of a subsystem via the QM/EFP (quantum mechanics/EFP) polarizable embedding scheme. The original formulation of the method assumes that the system can be separated, without breaking covalent bonds, into closed-shell fragments, such as solvent and solute molecules. Here, we present an extension of the EFP method to macromolecules (mEFP). Several schemes for breaking a large molecule into small fragments described by EFP are presented and benchmarked. We focus on the electronic properties of molecules embedded into a protein environment and consider ionization, electron-attachment, and excitation energies (single-point calculations only). The model systems include chromophores of green and red fluorescent proteins surrounded by several nearby amino acid residues and phenolate bound to the T4 lysozyme. All mEFP schemes show robust performance and accurately reproduce the reference full QM calculations. For further applications of mEFP, we recommend either the scheme in which the peptide is cut along the Cα-C bond, giving rise to one fragment per amino acid, or the scheme with two cuts per amino acid, along the Cα-C and Cα-N bonds. While using these fragmentation schemes, the errors in solvatochromic shifts in electronic energy differences (excitation, ionization, electron detachment, or electron-attachment) do not exceed 0.1 eV. The largest error of QM/mEFP against QM/EFP (no fragmentation of the EFP part) is 0.06 eV (in most cases, the errors are 0.01-0.02 eV). The errors in the QM/molecular mechanics calculations with standard point charges can be as large as 0.3 eV.
- Published
- 2016
30. The Effect of (-)-Epigallocatechin-3-Gallate on the Aβ Secondary Structure
- Author
-
Léon Beyer, Andreas Nabers, James C. Gumbart, Atanu Acharya, Julia Stockmann, Klaus Gerwert, and Victor S. Batista
- Subjects
Chemistry ,Stereochemistry ,Biophysics ,Gallate ,Protein secondary structure - Published
- 2020
31. Phenothiazine Radical Cation Excited States as Super-oxidants for Energy-Demanding Reactions
- Author
-
Joseph A. Christensen, Subhajyoti Chaudhuri, Atanu Acharya, Brian T. Phelan, Victor S. Batista, and Michael R. Wasielewski
- Subjects
010405 organic chemistry ,Relaxation (NMR) ,General Chemistry ,010402 general chemistry ,Photochemistry ,01 natural sciences ,Biochemistry ,Redox ,Catalysis ,0104 chemical sciences ,Photoexcitation ,chemistry.chemical_compound ,Colloid and Surface Chemistry ,chemistry ,Radical ion ,Phenothiazine ,Excited state ,Perylene ,Doublet state - Abstract
We demonstrate that the 10-phenyl-10H-phenothiazine radical cation (PTZ+•) has a manifold of excited doublet states accessible using visible and near-infrared light that can serve as super-photooxidants with excited-state potentials is excess of +2.1 V vs SCE to power energy demanding oxidation reactions. Photoexcitation of PTZ+• in CH3CN with a 517 nm laser pulse populates a Dn electronically excited doublet state that decays first to the unrelaxed lowest electronic excited state, D1′ (τ < 0.3 ps), followed by relaxation to D1 (τ = 10.9 ± 0.4 ps), which finally decays to D0 (τ = 32.3 ± 0.8 ps). D1′ can also be populated directly using a lower energy 900 nm laser pulse, which results in a longer D1′→D1 relaxation time (τ = 19 ± 2 ps). To probe the oxidative power of PTZ+• photoexcited doublet states, PTZ+• was covalently linked to each of three hole acceptors, perylene (Per), 9,10-diphenylanthracene (DPA), and 10-phenyl-9-anthracenecarbonitrile (ACN), which have oxidation potentials of 1.04, 1.27, and 1.6...
- Published
- 2018
32. Can TDDFT Describe Excited Electronic States of Naphthol Photoacids? A Closer Look with EOM-CCSD
- Author
-
Subhajyoti Chaudhuri, Victor S. Batista, and Atanu Acharya
- Subjects
Physics ,Excited electronic state ,010304 chemical physics ,Time-dependent density functional theory ,Configuration interaction ,010402 general chemistry ,01 natural sciences ,0104 chemical sciences ,Computer Science Applications ,Matrix (mathematics) ,Coupled cluster ,Excited state ,0103 physical sciences ,Physics::Atomic and Molecular Clusters ,Density functional theory ,Physics::Chemical Physics ,Physical and Theoretical Chemistry ,Atomic physics ,Excitation - Abstract
The 1Lb and 1La excited states of naphthols are characterized by using time-dependent density functional theory (TDDFT), configuration interaction with singles (CIS), and equation-of-motion coupled cluster singles and doubles (EOM-CCSD) methods. TDDFT fails dramatically at predicting the energy and ordering of the 1La and 1Lb excited states as observed experimentally, while EOM-CCSD accurately predicts the excited states as characterized by natural transition orbital analysis. The limitations of TDDFT are attributed to the absence of correlation from doubly excited configurations as well as the inconsistent description of excited electronic states of naphthol photoacids revealed by excitation analysis based on the one-electron transition density matrix.
- Published
- 2018
33. Is the Supporting Information the Venue for Reproducibility and Transparency?
- Author
-
Benjamin Rudshteyn, Atanu Acharya, and Victor S. Batista
- Subjects
0301 basic medicine ,Information management ,Reproducibility ,Magnetic Resonance Spectroscopy ,Computer science ,010405 organic chemistry ,Information Management ,Reproducibility of Results ,Molecular Dynamics Simulation ,010402 general chemistry ,Engineering physics ,Transparency (behavior) ,01 natural sciences ,0104 chemical sciences ,Surfaces, Coatings and Films ,Electronic, Optical and Magnetic Materials ,03 medical and health sciences ,030104 developmental biology ,General Energy ,Materials Chemistry ,Humans ,Physical and Theoretical Chemistry ,Software - Published
- 2017
34. Photoinduced Chemistry in Fluorescent Proteins: Curse or Blessing?
- Author
-
Ksenia B. Bravaya, Anna I. Krylov, Konstantin A. Lukyanov, Atanu Acharya, Bella L. Grigorenko, Alexey M. Bogdanov, and Alexander V. Nemukhin
- Subjects
0301 basic medicine ,Photoisomerization ,Chemistry ,Stereochemistry ,Photochemistry ,Electrons ,General Chemistry ,010402 general chemistry ,01 natural sciences ,Fluorescence ,0104 chemical sciences ,Green fluorescent protein ,03 medical and health sciences ,Electron transfer ,Luminescent Proteins ,030104 developmental biology ,Isomerism ,Covalent bond ,Fluorescent protein ,Protons ,Phototoxicity ,Quantum - Abstract
Photoinduced reactions play an important role in the photocycle of fluorescent proteins from the green fluorescent protein (GFP) family. Among such processes are photoisomerization, photooxidation/photoreduction, breaking and making of covalent bonds, and excited-state proton transfer (ESPT). Many of these transformations are initiated by electron transfer (ET). The quantum yields of these processes vary significantly, from nearly 1 for ESPT to 10–4–10–6 for ET. Importantly, even when quantum yields are relatively small, at the conditions of repeated illumination the overall effect is significant. Depending on the task at hand, fluorescent protein photochemistry is regarded either as an asset facilitating new applications or as a nuisance leading to the loss of optical output. The phenomena arising due to phototransformations include (i) large Stokes shifts, (ii) photoconversions, photoactivation, and photoswitching, (iii) phototoxicity, (iv) blinking, (v) permanent bleaching, and (vi) formation of long-l...
- Published
- 2016
35. Overall burden of under-nutrition measured by a Composite Index in rural pre-school children in Purba Medinipur, West Bengal, India
- Author
-
Atanu Acharya, Gopal Chandra Mandal, and Kaushik Bose
- Subjects
education.field_of_study ,Health (social science) ,business.industry ,Population ,Anthropometry ,medicine.disease ,Child development ,Child mortality ,Malnutrition ,Anthropology ,medicine ,medicine.symptom ,Underweight ,Composite index ,education ,business ,Wasting ,Demography - Abstract
Malnutrition is a leading cause of child mortality in India. To counteract this problem, a nutrition supplementation programme has been operating under the Integrated Child Development Service (ICDS) scheme in India since 1975. Recently, the Composite Index of Anthropometric Failure (CIAF) has been implemented to measure the seriousness and severity of overall under-nutrition in a population. Since this index presents a more complete picture than the previous three conventional measures. CIAF is utililized in this study which focuses on the overall burden of under-nutrition determination in pre-school children in Purba Medinipur, West Bengal, India. Our study was conducted in 10 Integrated Child Development Service (ICDS) centres, commonly known as “Anganwadi”, in the villages of the Argoal Gram Panchayat at Patashpur – II block. The total sample of 225 Bengalee ethnic children aged between 3 and 6 years was composed of 115 girls and 110 boys. The overall age and gender-combined prevalence of stunting, underweight and wasting recorded was 30.7%, 42.7% and 12.0%, respectively, and these rates were considered high (30–39%), very high (≥ 40%) and high (10–14%), respectively. CIAF results revealed the same trend, with 50.2% of these children affected by anthropometric failure, with the prevalence of underweight, wasting and CIAF higher in boys than in girls. This 50.2% CIAF result highlighted that approximately half the study children were undernourished. Since this figure is much higher than that estimated by any of the three conventional indicators,, CIAF has thus proven a far better indicator in assessing the overall burden of under-nutrition in a population. The nutritional status of the children in this study requires serious remedial action.
- Published
- 2013
36. Turning On and Off Photoinduced Electron Transfer in Fluorescent Proteins by π-Stacking, Halide Binding, and Tyr145 Mutations
- Author
-
Konstantin A. Lukyanov, Anastasia V. Mamontova, Anna I. Krylov, Anastasia V. Titelmayer, Anatoly B. Kolomeisky, Atanu Acharya, Ksenia B. Bravaya, and Alexey M. Bogdanov
- Subjects
0301 basic medicine ,Bromides ,Models, Molecular ,Green Fluorescent Proteins ,Stacking ,Plasma protein binding ,010402 general chemistry ,Photochemistry ,01 natural sciences ,Biochemistry ,Catalysis ,Photoinduced electron transfer ,Green fluorescent protein ,03 medical and health sciences ,Electron transfer ,Fluorides ,Colloid and Surface Chemistry ,Bacterial Proteins ,Chlorides ,Humans ,chemistry.chemical_classification ,Chemistry ,General Chemistry ,Chromophore ,Electron acceptor ,Iodides ,Photochemical Processes ,Fluorescence ,0104 chemical sciences ,Molecular Docking Simulation ,Luminescent Proteins ,030104 developmental biology ,HEK293 Cells ,Microscopy, Fluorescence ,Mutation ,Mutagenesis, Site-Directed ,Thermodynamics ,Tyrosine ,Oxidation-Reduction ,Protein Binding - Abstract
Photoinduced electron transfer in fluorescent proteins from the GFP family can be regarded either as an asset facilitating new applications or as a nuisance leading to the loss of optical output. Photooxidation commonly results in green-to-red photoconversion called oxidative redding. We discovered that yellow FPs do not undergo redding; however, the redding is restored upon halide binding. Calculations of the energetics of one-electron oxidation and possible electron transfer (ET) pathways suggested that excited-state ET proceeds through a hopping mechanism via Tyr145. In YFPs, the π-stacking of the chromophore with Tyr203 reduces its electron-donating ability, which can be restored by halide binding. Point mutations confirmed that Tyr145 is a key residue controlling ET. Substitution of Tyr145 by less-efficient electron acceptors resulted in highly photostable mutants. This strategy (i.e., calculation and disruption of ET pathways by mutations) may represent a new approach toward enhancing photostability of FPs.
- Published
- 2016
37. Photoinduced Redox Reactions in Biologically Relevant Systems
- Author
-
Atanu Acharya
- Published
- 2016
- Full Text
- View/download PDF
38. Toward understanding the redox properties of model chromophores from the green fluorescent protein family: an interplay between conjugation, resonance stabilization, and solvent effects
- Author
-
Subodh Tiwari, Anna I. Krylov, Debashree Ghosh, and Atanu Acharya
- Subjects
Quantitative Biology::Biomolecules ,Physics::Biological Physics ,Molecular Structure ,Chemistry ,Quantitative Biology::Molecular Networks ,Green Fluorescent Proteins ,Chromophore ,Photochemistry ,Redox ,Surfaces, Coatings and Films ,Green fluorescent protein ,Quantitative Biology::Subcellular Processes ,Solubility ,Computational chemistry ,Materials Chemistry ,Solvents ,Quantum Theory ,Thermodynamics ,Density functional theory ,Physical and Theoretical Chemistry ,Solvent effects ,Oxidation-Reduction - Abstract
The redox properties of model chromophores from the green fluorescent protein family are characterized computationally using density functional theory with a long-range corrected functional, the equation-of-motion coupled-cluster method, and implicit solvation models. The analysis of electron-donating abilities of the chromophores reveals an intricate interplay between the size of the chromophore, conjugation, resonance stabilization, presence of heteroatoms, and solvent effects. Our best estimates of the gas-phase vertical/adiabatic detachment energies of the deprotonated (i.e., anionic) model red, green, and blue chromophores are 3.27/3.15, 2.79/2.67, and 2.75/2.35 eV, respectively. Vertical/adiabatic ionization energies of the respective protonated (i.e., neutral) species are 7.64/7.35, 7.38/7.15, and 7.70/7.32 eV, respectively. The standard reduction potentials (E(red)(0)) of the anionic (Chr•/Chr–) and neutral (Chr+•/Chr) model chromophores in acetonitrile are 0.34/1.40 V (red), 0.22/1.24 V (green), and −0.12/1.02 V (blue), suggesting, counterintuitively, that the red chromophore is more difficult to oxidize than the green and blue ones (in both neutral and deprotonated forms). The respective redox potentials in water follow a similar trend but are more positive than the acetonitrile values.
- Published
- 2012
39. Characterization of the particles produced by exposure of ribosomal subunits to urea
- Author
-
Peter B. Moore, Atanu Acharya, and Jerome A. Langer
- Subjects
Binding Sites ,Chemistry ,Protein subunit ,Ribonucleoprotein particle ,Dithionitrobenzoic Acid ,Ribosomal RNA ,medicine.disease_cause ,Biochemistry, Genetics and Molecular Biology (miscellaneous) ,chemistry.chemical_compound ,Biochemistry ,Bacterial Proteins ,Ionic strength ,Reagent ,Mole ,medicine ,Urea ,Escherichia coli ,Ribosomes ,Protein Binding - Abstract
When Escherichia coli 50-S ribosomal subunits are treated with increasing concentrations of urea partial deproteination occurs. Furthermore, we observed that the number of sulfhydryl groups which react with Ellman's reagent is a sigmoidal function of the urea concentration. These results are similar to those previously reported for the 30-S subunit (Acharya, A.S. and Moore, P.B. (1973) J. Mol. Biol. 76, 207–221). For both subunits we identify the proteins which dissociate (split proteins) or are recoverable in a ribonucleoprotein particle (core proteins) under the action of 6 M urea in a buffer of moderate ionic strength.
Catalog
Discovery Service for Jio Institute Digital Library
For full access to our library's resources, please sign in.