scholarly journals Computational investigation on the role of C-Terminal of human albumin on the dimerization of Aβ1-42 peptide

2020 ◽  
Vol 10 (1) ◽  
pp. 4944-4955 ◽  
Keyword(s):  
Computational Study ◽  
Binding Free Energy ◽  
Conformational Dynamics ◽  
Human Albumin ◽  
Potential Of Mean Force ◽  
Amber Force Field ◽  
Aβ Aggregation ◽  
The Difference ◽  
Dynamics Simulations

Alzheimer’s disease (AD) is characterized by the presence of Amyloid-beta (Aβ) peptide, which has the propensity to fold into β-sheets under stress forming aggregated amyloid plaques. Nowadays many studies have focused on the development of novel, specific therapeutic strategies to slow down Aβ aggregation or control preformed aggregates. Albumin, the most abundant protein in the cerebrospinal fluid, was reported to bind Aβ impeding its aggregation. Recently, it has been reported that C-terminal (CTerm) of Human Albumin binds with Aβ1-42, impairs Aβ aggregation and promotes disassembly of Aβ aggregates protecting neurons. In this computational study, we have investigated the effect of CTerm on the conformational dynamics and the aggregation propensity of Aβ1-42 peptide. We have performed molecular dynamics simulations on the Aβ1-42-Aβ1-42 homodimer and Aβ1-42-CTerm of albumin heterodimer using the AMBER force field ff99SBildn. From the Potential of mean force (PMF) study and Binding free energy (BFE) analysis, we observed the association of Aβ1-42 peptide monomer with itself in the form of homodimer to be stronger than its association with the CTerm in the heterodimer complex. The difference in the number of residues in the Aβ1-42 peptide monomer (42 AAs) and CTerm (35 AAs) may be probable reason for the difference in association between the monomeric units in corresponding homodimer and heterodimer complexes. But even then CTerm shows a significant effect on the dimerization of Aβ1-42 peptide. Our findings therefore suggest that CTerm can be used for the disassembly of Aβ1-42 peptide monomer.

scholarly journals Promising Acyclovir and its derivatives to inhibit the protease of SARS-CoV-2: Molecular Docking and Molecular Dynamics simulations

2020 ◽  
Author(s):  
Durgesh Kumar ◽  
Kamlesh Kumari ◽  
Indra Bahadur ◽  
Prashant Singh
Keyword(s):  
Molecular Dynamics ◽  
Molecular Docking ◽  
Molecular Dynamics Simulations ◽  
Binding Free Energy ◽  
Antiviral Drug ◽  
Amber Force Field ◽  
New Beginning ◽  
Dynamics Simulations ◽  
Cytomegalovirus Infections ◽  
Relative Change

Abstract Till date, more than 40 million people are affected throughout the world due to the COVID-19. Therefore, there is an urgency to find a solution to cure this infection. It is is due to the SARS-CoV-2 infection and the authors have targetted the protease of the SARS-CoV-2 so the infection will not spread. Herein, the authors have selected the antiviral drug, acyclovir for the inhibition of protease of the SARS-CoV-2. Acyclovir is a popular and selective antiherpes agent and started a new beginning for the viral infection. The other name of acyclovir is aciclovir and is being used in the treatment of chickenpox, and shingles. Further, it can be used in avoidance of cytomegalovirus infections. Even, acyclovir can used to cure the patients suffering from cold scores, shingles and also decreases the pain.In the present work, acyclovir (CMPD1) and its two derivatives, the first derivative is Ganciclovir (CMPD2) and the second derivative is (CMPD3). These three molecules were used to inhibit the protease of SARS-CoV-2. It was studied through the molecular docking, molecular dynamics simulations etc. Herein, simulations method were used to calculate relative change in binding free energy under the influence of Amber force field through MM-GBSA. The structural behavior of complex system with acyclovir and its derivatives were observed in term of RMSD and RMSF for all residues. Authors observed that complex of CMPD3 with the protease is stable and has less fluctuation than the native protease. Further, CMPD3 follow the creteria of all drug likeness term and it showed good activity against SARS-CoV-2. It was suggested that CMPD3 may be used as a inhibitor for coronavirus activity to protect life of human being in world.

scholarly journals Molecular determinant of substrate binding and specificity of cytochrome P450 2J2

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Liang Xu ◽  
Liao Y. Chen
Keyword(s):  
Arachidonic Acid ◽  
Cytochrome P450 ◽  
Active Site ◽  
Structural Model ◽  
Substrate Binding ◽  
Conformational Dynamics ◽  
Structural Basis ◽  
Molecular Determinant ◽  
Dynamics Simulations

AbstractCytochrome P450 2J2 (CYP2J2) is responsible for the epoxidation of endogenous arachidonic acid, and is involved in the metabolism of exogenous drugs. To date, no crystal structure of CYP2J2 is available, and the proposed structural basis for the substrate recognition and specificity in CYP2J2 varies with the structural models developed using different computational protocols. In this study, we developed a new structural model of CYP2J2, and explored its sensitivity to substrate binding by molecular dynamics simulations of the interactions with chemically similar fluorescent probes. Our results showed that the induced-fit binding of these probes led to the preferred active poses ready for the catalysis by CYP2J2. Divergent conformational dynamics of CYP2J2 due to the binding of each probe were observed. However, a stable hydrophobic clamp composed of residues I127, F310, A311, V380, and I487 was identified to restrict any substrate access to the active site of CYP2J2. Molecular docking of a series of compounds including amiodarone, astemizole, danazol, ebastine, ketoconazole, terfenadine, terfenadone, and arachidonic acid to CYP2J2 confirmed the role of those residues in determining substrate binding and specificity of CYP2J2. In addition to the flexibility of CYP2J2, the present work also identified other factors such as electrostatic potential in the vicinity of the active site, and substrate strain energy and property that have implications for the interpretation of CYP2J2 metabolism.

scholarly journals Altered structure and dynamics of pathogenic cytochrome c variants correlate with increased apoptotic activity

2020 ◽  
Author(s):  
Matthias Fellner ◽  
Rinky Parakra ◽  
Kirstin O. McDonald ◽  
Itamar Kass ◽  
Guy N.L. Jameson ◽  
...  
Keyword(s):  
Peroxidase Activity ◽  
Conformational Dynamics ◽  
Cellular Processes ◽  
Pathogenic Variants ◽  
Alkaline Transition ◽  
Apoptotic Activity ◽  
Dynamics Simulations ◽  
And Function ◽  
Platelet Formation

AbstractMutation of cytochrome c in humans causes mild autosomal dominant thrombocytopenia. The role of cytochrome c in platelet formation, and molecular mechanism underlying the association of cytochrome c mutations with thrombocytopenia remains unknown, although a gain-of-function is most likely. Cytochrome c contributes to several cellular processes, with exchange between conformational states proposed to regulate changes in function. Here we use experimental and computational approaches to determine whether pathogenic variants share changes in structure and function, and to understand how these changes might occur. We find that three pathogenic variants (G41S, Y48H, A51V) cause an increase in apoptosome activation and peroxidase activity. Molecular dynamics simulations of these variants, and two non-naturally occurring variants (G41A, G41T), indicate that increased apoptosome activation correlates with increased overall flexibility of cytochrome c, particularly movement of the Ω loops. This suggests that the binding of cytochrome c to apoptotic protease activating factor-1 (Apaf-1) may involve an “induced fit” mechanism which is enhanced in the more conformationally mobile variants. In contrast, peroxidase activity did not significantly correlate with protein dynamics suggesting that the mechanism by which the variants alter peroxidase activity is not related to the conformation dynamics of the hexacoordinate heme Fe state of cytochrome c analyzed in the simulations. Recent suggestions that conformational mobility of specific regions of cytochrome c underpins changes in reduction potential and the alkaline transition pK were not supported. These data highlight that conformational dynamics of cytochrome c drives some but not all of its properties and activities.

scholarly journals Computational study of the dissolution of cellulose into single chains: the role of the solvent and agitation

Cellulose ◽  
2022 ◽  
Author(s):  
Eivind Bering ◽  
Jonathan Ø. Torstensen ◽  
Anders Lervik ◽  
Astrid S. de Wijn
Keyword(s):  
Molecular Dynamics ◽  
Molecular Dynamics Simulations ◽  
Hydrophobic Interactions ◽  
Computational Study ◽  
Pure Water ◽  
Solvent Mixture ◽  
Dissolution Mechanism ◽  
Dynamics Simulations ◽  
External Forces

Abstract We investigate the dissolution mechanism of cellulose using molecular dynamics simulations in both water and a mixture solvent consisting of water with Na$$^+$$ + , OH$$^-$$ - and urea. As a first computational study of its kind, we apply periodic external forces that mimic agitation of the suspension. Without the agitation, the bundles do not dissolve, neither in water nor solvent. In the solvent mixture the bundle swells with significant amounts of urea entering the bundle, as well as more water than in the bundles subjected to pure water. We also find that the mixture solution stabilizes cellulose sheets, while in water these immediately collapse into bundles. Under agitation the bundles dissolve more easily in the solvent mixture than in water, where sheets of cellulose remain that are bound together through hydrophobic interactions. Our findings highlight the importance of urea in the solvent, as well as the hydrophobic interactions, and are consistent with experimental results. Graphical abstract

Computational Investigation on the MDM2-Idasanutlin Interaction using the Potential of Mean Force method

2021 ◽  
Vol 15 ◽  
Author(s):  
Pundarikaksha Das ◽  
Venkata Satish Kumar Mattaparthi
Keyword(s):  
Free Energy ◽  
Binding Free Energy ◽  
Conformational Dynamics ◽  
Umbrella Sampling ◽  
Potential Of Mean Force ◽  
Negative Regulator ◽  
Energy Profile ◽  
Significant Information ◽  
Free Energy Profile ◽  
Binding Characteristics

Background: The Murine Double Minute 2 (MDM2) protein is a well-studied primary negative regulator of the tumor suppressor p53 molecule. Therefore, nowadays, many research studies have focused on the inhibition of MDM2 with potent inhibitors. Idasanutlin (RG7388) is a well-studied small molecule, the antagonist of MDM2 with potential antineoplastic activity. Nevertheless, the highly significant information about the free energy profile, intermediates, and the association of receptor and ligand components in the MDM2-idasanutlin complex remains unclear. Objective: To study the free energy profile of the MDM2-idasanutlin complex in terms of the Potential of Mean Force (PMF) method. Method: We have used the PMF method coupled with umbrella sampling simulations to generate the free energy profile for the association of N-Terminal Domain (NTD) of MDM2 and idasanutlin and a specific reaction coordinate for identifying transition states, intermediates as well as the relative stabilities of the endpoints. We have also determined the binding characteristics and interacting residues at the interface of the MDM2-idasanutlin complex from the Binding Free Energy (BFE) and Per Residue Energy Decomposition (PRED) analyses. Results: The PMF minima for the MDM2-idasanutlin complex was observed at a center of mass (CoM) distance of separation of 11 Å with dissociation energy of 17.5 kcal mol-1. As a function of the distance of separation of MDM2 from idasanutlin. We also studied the conformational dynamics and stability of the NTD of MDM2. We found a high binding affinity between MDM2 and idasanutlin (∆Grinding = -3.19 kcal mol-1). We found that in MDM2, the residues MET54, VAL67, and LEU58 provide the highest energy input for the interaction between MDM2 and idasanutlin. Conclusion: Our results in this study illustrate the significant structural and binding features of the MDM2-idasanutlin complex that may be useful in developing potent inhibitors of MDM2.

scholarly journals A Theoretical Approach to Demystify the Role of Copper Salts and O2 in the Mechanism of C-N Bond Cleavage and Nitrogen Transfer

2021 ◽  
Author(s):  
Boyli Ghosh ◽  
Ambar Banerjee ◽  
Lisa Roy ◽  
Rounak Nath ◽  
Rabindra Nath Manna Manna ◽  
...  
Keyword(s):  
Computational Study ◽  
Bond Cleavage ◽  
Nitrogen Transfer ◽  
Copper Salts ◽  
Cyanide Anion ◽  
Aryl Aldehydes ◽  
Bond Scission ◽  
Dynamics Simulations ◽  
Experimental Findings

<b>C≡N bond scission accomplished by protonation, reductive cleavage and metathesis techniques are well-known to execute nitrogen transfer reactions. Herein, we have conducted an extensive computational study, using DFT and molecular dynamics simulations, to unravel the mechanistic pathways traversed in CuCN and CuBr<sub>2</sub> promoted splitting of coordinated cyanide anion under a dioxygen atmosphere, which enables nitrogen transfer to various aldehydes. Our detailed electronic structure analysis using <i>ab initio</i> multi-reference CASSCF calculations reveal that both the promoters facilitate radical pathways, in agreement with the experimental findings. This is a unique instance of oxygen activation initiated by single electron transfer from the nitrile carbon, while the major driving force is the operation of the Cu<sup>II/I </sup>redox cycle. Our study reveals that the copper salts act as the “electron pool” in this unique nitrogen transfer reaction forming aryl nitrile from aryl aldehydes.</b><br>

scholarly journals A Theoretical Approach to Demystify the Role of Copper Salts and O2 in the Mechanism of C-N Bond Cleavage and Nitrogen Transfer

2021 ◽  
Author(s):  
Boyli Ghosh ◽  
Ambar Banerjee ◽  
Lisa Roy ◽  
Rounak Nath ◽  
Rabindra Nath Manna Manna ◽  
...  
Keyword(s):  
Computational Study ◽  
Bond Cleavage ◽  
Nitrogen Transfer ◽  
Copper Salts ◽  
Cyanide Anion ◽  
Aryl Aldehydes ◽  
Bond Scission ◽  
Dynamics Simulations ◽  
Experimental Findings

<b>C≡N bond scission accomplished by protonation, reductive cleavage and metathesis techniques are well-known to execute nitrogen transfer reactions. Herein, we have conducted an extensive computational study, using DFT and molecular dynamics simulations, to unravel the mechanistic pathways traversed in CuCN and CuBr<sub>2</sub> promoted splitting of coordinated cyanide anion under a dioxygen atmosphere, which enables nitrogen transfer to various aldehydes. Our detailed electronic structure analysis using <i>ab initio</i> multi-reference CASSCF calculations reveal that both the promoters facilitate radical pathways, in agreement with the experimental findings. This is a unique instance of oxygen activation initiated by single electron transfer from the nitrile carbon, while the major driving force is the operation of the Cu<sup>II/I </sup>redox cycle. Our study reveals that the copper salts act as the “electron pool” in this unique nitrogen transfer reaction forming aryl nitrile from aryl aldehydes.</b><br>

scholarly journals Beyond Shielding: The Roles of Glycans in SARS-CoV-2 Spike Protein

2020 ◽  
Author(s):  
Lorenzo Casalino ◽  
Zied Gaieb ◽  
Jory A. Goldsmith ◽  
Christy K. Hjorth ◽  
Abigail C. Dommer ◽  
...  
Keyword(s):  
Vaccine Development ◽  
Conformational Dynamics ◽  
Biological Data ◽  
S Protein ◽  
Angiotensin Converting Enzyme 2 ◽  
Conformational Plasticity ◽  
Host Cell Entry ◽  
Dynamics Simulations ◽  
Structural Insights

AbstractThe ongoing COVID-19 pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has resulted in more than 15,000,000 infections and 600,000 deaths worldwide to date. Antibody development efforts mainly revolve around the extensively glycosylated SARS-CoV-2 spike (S) protein, which mediates the host cell entry by binding to the angiotensin-converting enzyme 2 (ACE2). Similar to many other viruses, the SARS-CoV-2 spike utilizes a glycan shield to thwart the host immune response. Here, we built a full-length model of glycosylated SARS-CoV-2 S protein, both in the open and closed states, augmenting the available structural and biological data. Multiple microsecond-long, all-atom molecular dynamics simulations were used to provide an atomistic perspective on the roles of glycans, and the protein structure and dynamics. We reveal an essential structural role of N-glycans at sites N165 and N234 in modulating the conformational dynamics of the spike’s receptor binding domain (RBD), which is responsible for ACE2 recognition. This finding is corroborated by biolayer interferometry experiments, which show that deletion of these glycans through N165A and N234A mutations significantly reduces binding to ACE2 as a result of the RBD conformational shift towards the “down” state. Additionally, end-to-end accessibility analyses outline a complete overview of the vulnerabilities of the glycan shield of SARS-CoV-2 S protein, which may be exploited by therapeutic efforts targeting this molecular machine. Overall, this work presents hitherto unseen functional and structural insights into the SARS-CoV-2 S protein and its glycan coat, providing a strategy to control the conformational plasticity of the RBD that could be harnessed for vaccine development.

Computational study on the unbinding pathways of B-RAF inhibitors and its implication for the difference of residence time: insight from random acceleration and steered molecular dynamics simulations

2016 ◽  
Vol 18 (7) ◽  
pp. 5622-5629 ◽  
Author(s):  
Yuzhen Niu ◽  
Shuyan Li ◽  
Dabo Pan ◽  
Huanxiang Liu ◽  
Xiaojun Yao
Keyword(s):  
Molecular Dynamics ◽  
Molecular Dynamics Simulations ◽  
Residence Time ◽  
Computational Study ◽  
Steered Molecular Dynamics ◽  
The Difference ◽  
Random Acceleration ◽  
Dynamics Simulations

Random acceleration and steered molecular dynamics simulations reveal the unbinding pathway of B-RAF inhibitors and the difference in the residence time.

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