scholarly journals Online biophysical predictions for SARS-CoV-2 proteins

2021 ◽  
Vol 22 (1) ◽  
Author(s):  
Luciano Kagami ◽  
Joel Roca-Martínez ◽  
Jose Gavaldá-García ◽  
Pathmanaban Ramasamy ◽  
K. Anton Feenstra ◽  
...  
Keyword(s):  
Protein Sequence ◽  
Three Dimensional ◽  
Dimensional Structure ◽  
Static Structure ◽  
Homologous Proteins ◽  
Structure Based Drug Design ◽  
Protein Protein Interaction ◽  
Link Type ◽  
Dynamics Simulations ◽  
Β Sheet

Abstract Background The SARS-CoV-2 virus, the causative agent of COVID-19, consists of an assembly of proteins that determine its infectious and immunological behavior, as well as its response to therapeutics. Major structural biology efforts on these proteins have already provided essential insights into the mode of action of the virus, as well as avenues for structure-based drug design. However, not all of the SARS-CoV-2 proteins, or regions thereof, have a well-defined three-dimensional structure, and as such might exhibit ambiguous, dynamic behaviour that is not evident from static structure representations, nor from molecular dynamics simulations using these structures. Main We present a website (https://bio2byte.be/sars2/) that provides protein sequence-based predictions of the backbone and side-chain dynamics and conformational propensities of these proteins, as well as derived early folding, disorder, β-sheet aggregation, protein-protein interaction and epitope propensities. These predictions attempt to capture the inherent biophysical propensities encoded in the sequence, rather than context-dependent behaviour such as the final folded state. In addition, we provide the biophysical variation that is observed in homologous proteins, which gives an indication of the limits of their functionally relevant biophysical behaviour. Conclusion The https://bio2byte.be/sars2/ website provides a range of protein sequence-based predictions for 27 SARS-CoV-2 proteins, enabling researchers to form hypotheses about their possible functional modes of action.

scholarly journals Online biophysical predictions for SARS-CoV-2 proteins

2020 ◽  
Author(s):  
Luciano Kagami ◽  
Joel Roca-Martínez ◽  
Jose Gavaldá-García ◽  
Pathmanaban Ramasamy ◽  
K. Anton Feenstra ◽  
...  
Keyword(s):  
Three Dimensional ◽  
Dimensional Structure ◽  
Side Chain ◽  
Emergent Properties ◽  
Static Structure ◽  
Homologous Proteins ◽  
Structure Based Drug Design ◽  
Protein Protein Interaction ◽  
Dynamics Simulations ◽  
Β Sheet

AbstractThe SARS-CoV-2 virus, the causative agent of COVID-19, consists of an assembly of proteins that determine its infectious and immunological behavior, as well as its response to therapeutics. Major structural biology efforts on these proteins have already provided essential insights into the mode of action of the virus, as well as avenues for structure-based drug design. However, not all of the SARS-CoV-2 proteins, or regions thereof, have a well-defined three-dimensional structure, and as such might exhibit ambiguous, dynamic behaviour that is not evident from static structure representations, nor from molecular dynamics simulations using these structures. We here present a website (http://sars2.bio2byte.be/) that provides protein sequence-based predictions of the backbone and side-chain dynamics and conformational propensities of these proteins, as well as derived early folding, disorder, β-sheet aggregation and protein-protein interaction propensities. These predictions attempt to capture the ‘emergent’ properties of the proteins, so the inherent biophysical propensities encoded in the sequence, rather than context-dependent behaviour such as the final folded state. In addition, we provide an indication of the biophysical variation that is observed in homologous proteins, which give an indication of the limits of the functionally relevant biophysical behaviour of these proteins. With this website, we therefore hope to provide researchers with further clues on the behaviour of SARS-CoV-2 proteins.

scholarly journals Conformational Ensembles of Non-Coding Elements in the SARS-CoV-2 Genome from Molecular Dynamics Simulations

2020 ◽  
Author(s):  
Sandro Bottaro ◽  
Giovanni Bussi ◽  
Kresten Lindorff-Larsen
Keyword(s):  
Molecular Dynamics ◽  
Molecular Dynamics Simulations ◽  
Three Dimensional ◽  
Genomic Region ◽  
Dimensional Structure ◽  
Structure Based Drug Design ◽  
Stem Loop ◽  
Rna Molecules ◽  
Conformational Ensembles ◽  
Dynamics Simulations

The 5' untranslated region (UTR) of SARS-CoV-2 genome is a conserved, functional and structured genomic region consisting of several RNA stem-loop elements. While the secondary structure of such elements has been determined experimentally, their three-dimensional structure is not known yet. Here, we predict structure and dynamics of five RNA stem-loops in the 5'-UTR of SARS-CoV-2 by extensive atomistic molecular dynamics simulations, more than 0.5ms of aggregate simulation time, in combination with enhanced sampling techniques. We compare simulations with available experimental data, describe the resulting conformational ensembles, and identify the presence of specific structural rearrengements in apical and internal loops that may be functionally relevant. Our atomic-detailed structural predictions reveal a rich dynamics in these RNA molecules, could help the experimental characterisation of these systems, and provide putative three-dimensional models for structure-based drug design studies.

scholarly journals Aβ(1-42) tetramer and octamer structures reveal edge pores as a mechanism for membrane damage

2019 ◽  
Author(s):  
Sonia Ciudad ◽  
Eduard Puig ◽  
Thomas Botzanowski ◽  
Moeen Meigooni ◽  
Andres S. Arango ◽  
...  
Keyword(s):  
Lipid Bilayers ◽  
Membrane Damage ◽  
Three Dimensional ◽  
Dimensional Structure ◽  
Ion Permeation ◽  
The Core ◽  
Hydrophilic Residues ◽  
Dynamics Simulations ◽  
Β Sheet ◽  
Aβ Oligomer

AbstractThe formation of amyloid-beta (Aβ) oligomer pores in the membrane of neurons has been proposed as the means to explain neurotoxicity in Alzheimer’s disease (AD). It is therefore critical to characterize Aβ oligomer samples in membrane-mimicking environments. Here we present the first three-dimensional structure of an Aβ oligomer formed in dodecyl phosphocholine (DPC) micelles, namely an Aβ(1-42) tetramer. It comprises a β-sheet core made of six β-strands, connected by only two β-turns. The two faces of the β-sheet core are hydrophobic and surrounded by the membrane-mimicking environment. In contrast, the edges of the core are hydrophilic and are solvent-exposed. By increasing the concentration of Aβ(1-42), we prepared a sample enriched in Aβ(1-42) octamers, formed by two Aβ(1-42) tetramers facing each other forming a β-sandwich structure. Notably, samples enriched in Aβ(1-42) tetramers and octamers are both active in lipid bilayers and exhibit the same types of pore-like behaviour, but they show different occurrence rates. Remarkably, molecular dynamics simulations showed a new mechanism of membrane disruption in which water and ion permeation occurred through lipid-stabilized pores mediated by the hydrophilic residues located on the core β-sheets edges of the Aβ(1-42) tetramers and octamers.

scholarly journals Biochemical mechanism of action of a diketopiperazine inactivator of plasminogen activator inhibitor-1

2003 ◽  
Vol 373 (3) ◽  
pp. 723-732 ◽  
Author(s):  
Anja P. EINHOLM ◽  
Katrine E. PEDERSEN ◽  
Troels WIND ◽  
Paulina KULIG ◽  
Michael T. OVERGAARD ◽  
...  
Keyword(s):  
Plasminogen Activator ◽  
Therapeutic Target ◽  
Three Dimensional ◽  
Plasminogen Activator Inhibitor ◽  
Dimensional Structure ◽  
Plasminogen Activator Inhibitor 1 ◽  
Biochemical Basis ◽  
Β Sheet ◽  
Activator Inhibitor ◽  
Pai 1

XR5118 [(3Z,6Z)-6-benzylidine-3-(5-(2-dimethylaminoethyl-thio-))-2-(thienyl)methylene-2,5-dipiperazinedione hydrochloride] can inactivate the anti-proteolytic activity of the serpin plasminogen activator inhibitor-1 (PAI-1), a potential therapeutic target in cancer and cardiovascular diseases. Serpins inhibit their target proteases by the P1 residue of their reactive centre loop (RCL) forming an ester bond with the active-site serine residue of the protease, followed by insertion of the RCL into the serpin's large central β-sheet A. In the present study, we show that the RCL of XR5118-inactivated PAI-1 is inert to reaction with its target proteases and has a decreased susceptibility to non-target proteases, in spite of a generally increased proteolytic susceptibility of specific peptide bonds elsewhere in PAI-1. The properties of XR5118-inactivated PAI-1 were different from those of the so-called latent form of PAI-1. Alanine substitution of several individual residues decreased the susceptibility of PAI-1 to XR5118. The localization of these residues in the three-dimensional structure of PAI-1 suggested that the XR5118-induced inactivating conformational change requires mobility of α-helix F, situated above β-sheet A, and is in agreement with the hypothesis that XR5118 binds laterally to β-sheet A. These results improve our understanding of the unique conformational flexibility of serpins and the biochemical basis for using PAI-1 as a therapeutic target.

scholarly journals Solution structure of a defensin-like peptide from platypus venom

1999 ◽  
Vol 341 (3) ◽  
pp. 785-794 ◽  
Author(s):  
Allan M. TORRES ◽  
Xiuhong WANG ◽  
Jamie I. FLETCHER ◽  
Dianne ALEWOOD ◽  
Paul F. ALEWOOD ◽  
...  
Keyword(s):  
Sodium Channel ◽  
Dorsal Root ◽  
Solution Structure ◽  
Biological Function ◽  
Three Dimensional ◽  
Dimensional Structure ◽  
Structural Elements ◽  
Channel Currents ◽  
Β Sheet ◽  
310 Helix

Three defensin-like peptides (DLPs) were isolated from platypus venom and sequenced. One of these peptides, DLP-1, was synthesized chemically and its three-dimensional structure was determined using NMR spectroscopy. The main structural elements of this 42-residue peptide were an anti-parallel β-sheet comprising residues 15-18 and 37-40 and a small 310 helix spanning residues 10-12. The overall three-dimensional fold is similar to that of β-defensin-12, and similar to the sodium-channel neurotoxin ShI (Stichodactyla helianthusneurotoxin I). However, the side chains known to be functionally important in β-defensin-12 and ShI are not conserved in DLP-1, suggesting that it has a different biological function. Consistent with this contention, we showed that DLP-1 possesses no anti-microbial properties and has no observable activity on rat dorsal-root-ganglion sodium-channel currents.

scholarly journals Prediction of fluorophore brightness in designed mini fluorescence activating proteins

2021 ◽  
Author(s):  
Emma R. Hostetter ◽  
Jeffrey R. Keyes ◽  
Ivy Poon ◽  
Justin P. Nguyen ◽  
Jacob Nite ◽  
...  
Keyword(s):  
Protein Function ◽  
De Novo ◽  
Energy Landscape ◽  
Three Dimensional ◽  
Computational Design ◽  
Dimensional Structure ◽  
Bond Rotation ◽  
Beta Barrel ◽  
Angle Rotation ◽  
Dynamics Simulations

The de novo computational design of proteins with predefined three-dimensional structure is becoming much more routine due to advancements both in force fields and algorithms. However, creating designs with functions beyond folding is more challenging. In that regard, the recent design of small beta barrel proteins that activate the fluorescence of an exogenous small molecule chromophore (DFHBI) is noteworthy. These proteins, termed mini Fluorescence Activating Proteins (mFAPs), have been shown increase the brightness of the chromophore more than 100-fold upon binding to the designed ligand pocket. The design process created a large library of variants with different brightness levels but gave no rational explanation for why one variant was brighter than another. Here we use quantum mechanics and molecular dynamics simulations to investigate how molecular flexibility in the ground and excited states influences brightness. We show that the ability of the protein to resist dihedral angle rotation of the chromophore is critical for predicting brightness. Our simulations suggest that the mFAP/DFHBI complex has a rough energy landscape, requiring extensive ground-state sampling to achieve converged predictions of excited-state kinetics. While computationally demanding, this roughness suggests that mFAP protein function can be enhanced by reshaping the energy landscape towards states that better resist DFHBI bond rotation.

scholarly journals Amphotericin B Assembles into Seven-Molecule Ion Channels in Membrane Domain

2021 ◽  
Author(s):  
Yuichi Umegawa ◽  
Tomoya Yamamoto ◽  
Mayank Dixit ◽  
Kosuke Funahashi ◽  
Sangjae Seo ◽  
...  
Keyword(s):  
Amphotericin B ◽  
Three Dimensional ◽  
Dimensional Structure ◽  
Resonance Spectroscopy ◽  
Selective Toxicity ◽  
Drug Molecules ◽  
Conductive Channel ◽  
High Resolution Structure ◽  
Dynamics Simulations ◽  
Resolution Structure

Amphotericin B, a long-used antifungal drug, forms fungicidal ion-permeable channels across cell membranes. Using solid-state nuclear magnetic resonance spectroscopy and molecular dynamics simulations, we experimentally elucidated the three-dimensional structure of the molecular assemblies formed by this drug in membranes in the presence of the fungal sterol, ergosterol. A stable assembly of seven drug molecules was observed to form an ion conductive channel. The structure somewhat resembled the upper half of the barrel-stave model proposed in the 1970s but different substantially in the number of molecules and their arrangement. Based on the structure obtained, the aggregation of the channel assemblies in membranes was investigated and a mechanism was proposed in which complexation with ergosterol stabilizes the drug’s assemblies, leading to their aggregation, and in turn enhancing channel activity. The high-resolution structure is consistent with many previous findings, including structure-activity relationships of the drug, and the channel aggregation provides a more reasonable explanation for the selective toxicity of this drug to fungi.

scholarly journals Integrating NMR and simulations reveals motions in the UUCG tetraloop

2020 ◽  
Vol 48 (11) ◽  
pp. 5839-5848 ◽  
Author(s):  
Sandro Bottaro ◽  
Parker J Nichols ◽  
Beat Vögeli ◽  
Michele Parrinello ◽  
Kresten Lindorff-Larsen
Keyword(s):  
Experimental Data ◽  
Three Dimensional ◽  
Machine Learning Techniques ◽  
Dimensional Structure ◽  
Stable Conformation ◽  
Stem Loop ◽  
Loop Region ◽  
Simple Model System ◽  
Nuclear Overhauser ◽  
Dynamics Simulations

Abstract We provide an atomic-level description of the structure and dynamics of the UUCG RNA stem–loop by combining molecular dynamics simulations with experimental data. The integration of simulations with exact nuclear Overhauser enhancements data allowed us to characterize two distinct states of this molecule. The most stable conformation corresponds to the consensus three-dimensional structure. The second state is characterized by the absence of the peculiar non-Watson–Crick interactions in the loop region. By using machine learning techniques we identify a set of experimental measurements that are most sensitive to the presence of non-native states. We find that although our MD ensemble, as well as the consensus UUCG tetraloop structures, are in good agreement with experiments, there are remaining discrepancies. Together, our results show that (i) the MD simulation overstabilize a non-native loop conformation, (ii) eNOE data support its presence with a population of ≈10% and (iii) the structural interpretation of experimental data for dynamic RNAs is highly complex, even for a simple model system such as the UUCG tetraloop.

scholarly journals The Structure of Bypass of Forespore C, an Intercompartmental Signaling Factor during Sporulation in Bacillus

2005 ◽  
Vol 280 (43) ◽  
pp. 36214-36220 ◽  
Author(s):  
Hayley M. Patterson ◽  
James A. Brannigan ◽  
Simon M. Cutting ◽  
Keith S. Wilson ◽  
Anthony J. Wilkinson ◽  
...  
Keyword(s):  
Rna Polymerase ◽  
Mother Cell ◽  
Asymmetric Cell Division ◽  
Three Dimensional ◽  
Dimensional Structure ◽  
Coat Proteins ◽  
Terminal Domain ◽  
Spore Coat Proteins ◽  
Α Helix ◽  
Β Sheet

Sporulation in Bacillus subtilis begins with an asymmetric cell division giving rise to smaller forespore and larger mother cell compartments. Different programs of gene expression are subsequently directed by compartment-specific RNA polymerase σ-factors. In the final stages, spore coat proteins are synthesized in the mother cell under the control of RNA polymerase containing σK, (EσK). σK is synthesized as an inactive zymogen, pro-σK, which is activated by proteolytic cleavage. Processing of pro-σK is performed by SpoIVFB, a metalloprotease that resides in a complex with SpoIVFA and bypass of forespore (Bof)A in the outer forespore membrane. Ensuring coordination of events taking place in the two compartments, pro-σK processing in the mother cell is delayed until appropriate signals are received from the forespore. Cell-cell signaling is mediated by SpoIVB and BofC, which are expressed in the forespore and secreted to the intercompartmental space where they regulate pro-σK processing by mechanisms that are not yet fully understood. Here we present the three-dimensional structure of BofC determined by solution state NMR. BofC is a monomer made up of two domains. The N-terminal domain, containing a four-stranded β-sheet onto one face of which an α-helix is packed, closely resembles the third immunoglobulin-binding domain of protein G from Streptococcus. The C-terminal domain contains a three-stranded β-sheet and three α-helices in a novel domain topology. The sequence connecting the domains contains a conserved DISP motif to which mutations that affect BofC activity map. Possible roles for BofC in the σK checkpoint are discussed in the light of sequence and structure comparisons.

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