scholarly journals Flap dynamics in pepsin-like aspartic proteases: a computational perspective using Plasmepsin-II and BACE-1 as model systems

2020 ◽  
Author(s):  
Soumendranath Bhakat ◽  
Pär Söderhjelm
Keyword(s):  
Dynamic Equilibrium ◽  
Sequence Similarity ◽  
Experimental Studies ◽  
Md Simulations ◽  
Model Systems ◽  
Side Chain ◽  
Aspartic Proteases ◽  
Plasmepsin Ii ◽  
Normal States ◽  
Bace 1

AbstractFlexibility of β hairpin structure known as flap plays a key role in catalytic activity and substrate intake in pepsin-like aspartic proteases. Most of these enzymes share structural and sequence similarity. Tyrosine is a conserved residue present in the flap region of pepsin-like aspartic proteases. In apo protease, tyrosine remains in a dynamic equilibrium between normal and flipped states due to rotation of χ1 angle (distributions of the χ1 angle centred around radian or radian are denoted as normal, whereas distribution centred around ±π radian is denoted as flipped). In this study, we have used apo Plm-II and BACE-1 as model systems. Independent MD simulations starting with Plm-II and BACE-1 remained stuck either in normal or flipped state. Metadynamics simulations using torsion angles (χ1 and χ2 of Tyr) as CVs sampled transition between normal and flipped states. Qualitatively, flipped and normal states predicted to be equally populated. These states were stabilised by H-bond interactions to tryptophan (normal) and catalytic aspartate (flipped) respectively. Further, mutation of tyrosine to an amino-acid with smaller side-chain, such as alanine; reduced flap flexibility and resulted in a flap collapse. This is in accordance with previous experimental studies which showed that mutation to alanine resulted in loss of activity in pepsin-like aspartic proteases. Using apo plasmepsin-II and BACE-1 as model systems, we have hypothesised that the rotation of tyrosine side-chain is the key movement which governs the flap dynamics in all pepsin-like aspartic proteases.

Adsorption Conformation of Comb-Shaped Polycarboxylate Ethers on Ettringite (100) Surface: An Atomic Scales Simulation

2020 ◽  
pp. 2150007
Author(s):  
Hongxia Zhao ◽  
Yong Yang ◽  
Shenyou Song ◽  
Xin Shu ◽  
Weile Chen ◽  
...  
Keyword(s):  
Dynamic Equilibrium ◽  
Ion Pairs ◽  
Md Simulations ◽  
Distribution Functions ◽  
Side Chain ◽  
Side Chains ◽  
Distribution Profile ◽  
Coverage Area ◽  
Carboxylate Groups ◽  
Adsorption Energies

The adsorption of five polycarboxylate ethers (PCEs) oligomers with different side-chain number and side-chain length on the ettringite (100) surface in explicit solution is studied by all-atom molecular dynamics (MD) simulations. The adsorption conformations, adsorption energies, the radial distribution functions (RDF) between PCEs and ettringite surface and density distribution profile of water perpendicular to the substrate are analyzed. After dynamic equilibrium, negatively charged carboxylate groups are absorbed on the surface of the disordered ettringite crystal and the side-chains are extended to solution. The influence of the number of side-chain on the adsorption strength of PCEs on the ettringite (100) surface is more significant than that of the length of side-chain. The less number of grafted side-chains, the weaker electrostatic shielding, the electrostatic interaction between PCEs and ettringite (100) surface is stronger, which is favorable for the adsorption. The conformation of adsorbed PCEs is closely related to the length of side chain. The greater the length of side-chains is, the larger will be the coverage area of PCE on surface and the degree of water reduction. The mechanism of adsorption of PCEs on ettringite surface is concluded and the major contribution to the adsorption includes ion pairs, hydrogen bonds and an entropic compensation.

Structure, stability and folding of the α-helix

2001 ◽  
Vol 68 ◽  
pp. 95-110 ◽  
Author(s):  
Andrew J. Doig ◽  
Charles D. Andrew ◽  
Duncan A. E. Cochran ◽  
Eleri Hughes ◽  
Simon Penel ◽  
...  
Keyword(s):  
Hydrogen Bonding ◽  
Hydrophobic Interactions ◽  
Data Bank ◽  
Site Directed Mutagenesis ◽  
Model Systems ◽  
Side Chain ◽  
Structure Stability ◽  
Helical Peptides ◽  
Vast Number ◽  
Α Helix

Pauling first described the α-helix nearly 50 years ago, yet new features of its structure continue to be discovered, using peptide model systems, site-directed mutagenesis, advances in theory, the expansion of the Protein Data Bank and new experimental techniques. Helical peptides in solution form a vast number of structures, including fully helical, fully coiled and partly helical. To interpret peptide results quantitatively it is essential to use a helix/coil model that includes the stabilities of all these conformations. Our models now include terms for helix interiors, capping, side-chain interactions, N-termini and 310-helices. The first three amino acids in a helix (N1, N2 and N3) and the preceding N-cap are unique, as their amide NH groups do not participate in backbone hydrogen bonding. We surveyed their structures in proteins and measured their amino acid preferences. The results are predominantly rationalized by hydrogen bonding to the free NH groups. Stabilizing side-chain-side-chain energies, including hydrophobic interactions, hydrogen bonding and polar/non-polar interactions, were measured accurately in helical peptides. Helices in proteins show a preference for having approximately an integral number of turns so that their N- and C-caps lie on the same side. There are also strong periodic trends in the likelihood of terminating a helix with a Schellman or αL C-cap motif. The kinetics of α-helix folding have been studied with stopped-flow deep ultraviolet circular dichroism using synchrotron radiation as the light source; this gives a far superior signal-to-noise ratio than a conventional instrument. We find that poly(Glu), poly(Lys) and alanine-based peptides fold in milliseconds, with longer peptides showing a transient overshoot in helix content.

scholarly journals The role of side chains in the interaction of new antitumor pyrimidoacridinetriones with DNA: molecular dynamics simulations.

2000 ◽  
Vol 47 (1) ◽  
pp. 47-57 ◽  
Author(s):  
J Mazerski ◽  
I Antonini ◽  
S Martelli
Keyword(s):  
Molecular Dynamics ◽  
Rational Design ◽  
Md Simulations ◽  
Ring System ◽  
Side Chain ◽  
Side Chains ◽  
Intercalation Complex ◽  
Highly Active ◽  
Simulation Techniques ◽  
Dynamics Simulations

Pyrimidoacridinetriones (PATs) are a new group of highly active antitumor compounds. It seems reasonable to assume that, like for some other acridine derivatives, intercalation into DNA is a necessary, however not a sufficient condition for antitumor activity of these compounds. Rational design of new compounds of this chemotype requires knowledge about the structure of the intercalation complex, as well as about interactions responsible for its stability. Computer simulation techniques such as molecular dynamics (MD) may provide valuable information about these problems. The results of MD simulations performed for three rationally selected PATs are presented in this paper. The compounds differ in the number and position of side chains. Each of the compounds was simulated in two systems: i) in water, and ii) in the intercalation complex with the dodecamer duplex d(GCGCGCGCGCGC)2. The orientation of the side chain in relation to the ring system is determined by the position of its attachment. Orientation of the ring system inside the intercalation cavity depends on the number and position of side chain(s). The conformations of the side chain(s) of all PATs studied in the intercalation complex were found to be very similar to those observed in water.

scholarly journals Pan-Genome of the Genus Streptomyces and Prioritization of Biosynthetic Gene Clusters With Potential to Produce Antibiotic Compounds

2021 ◽  
Vol 12 ◽  
Author(s):  
Carlos Caicedo-Montoya ◽  
Monserrat Manzo-Ruiz ◽  
Rigoberto Ríos-Estepa
Keyword(s):  
Comparative Genomics ◽  
Sequence Similarity ◽  
Experimental Studies ◽  
Gene Clusters ◽  
Antibiotic Activity ◽  
Genomic Diversity ◽  
Biosynthetic Gene ◽  
Biosynthetic Gene Clusters ◽  
Genus Streptomyces ◽  
Pan Genome

Species of the genus Streptomyces are known for their ability to produce multiple secondary metabolites; their genomes have been extensively explored to discover new bioactive compounds. The richness of genomic data currently available allows filtering for high quality genomes, which in turn permits reliable comparative genomics studies and an improved prediction of biosynthetic gene clusters (BGCs) through genome mining approaches. In this work, we used 121 genome sequences of the genus Streptomyces in a comparative genomics study with the aim of estimating the genomic diversity by protein domains content, sequence similarity of proteins and conservation of Intergenic Regions (IGRs). We also searched for BGCs but prioritizing those with potential antibiotic activity. Our analysis revealed that the pan-genome of the genus Streptomyces is clearly open, with a high quantity of unique gene families across the different species and that the IGRs are rarely conserved. We also described the phylogenetic relationships of the analyzed genomes using multiple markers, obtaining a trustworthy tree whose relationships were further validated by Average Nucleotide Identity (ANI) calculations. Finally, 33 biosynthetic gene clusters were detected to have potential antibiotic activity and a predicted mode of action, which might serve up as a guide to formulation of related experimental studies.

scholarly journals Ecological Immunology of mosquito-malaria interactions: Of non-natural versus natural model systems and their inferences

Parasitology ◽  
2009 ◽  
Vol 136 (14) ◽  
pp. 1935-1942 ◽  
Author(s):  
F. TRIPET
Keyword(s):  
Immune Responses ◽  
Population Biology ◽  
Experimental Studies ◽  
Natural Populations ◽  
Population Level ◽  
Model Systems ◽  
Ecological Immunology ◽  
Experimental Systems ◽  
Evolutionary Context ◽  
And Function

SUMMARYThere has been a recent shift in the literature on mosquito/Plasmodium interactions with an increasingly large number of theoretical and experimental studies focusing on their population biology and evolutionary processes. Ecological immunology of mosquito-malaria interactions – the study of the mechanisms and function of mosquito immune responses to Plasmodium in their ecological and evolutionary context – is particularly important for our understanding of malaria transmission and how to control it. Indeed, describing the processes that create and maintain variation in mosquito immune responses and parasite virulence in natural populations may be as important to this endeavor as describing the immune responses themselves. For historical reasons, Ecological Immunology still largely relies on studies based on non-natural model systems. There are many reasons why current research should favour studies conducted closer to the field and more realistic experimental systems whenever possible. As a result, a number of researchers have raised concerns over the use of artificial host-parasite associations to generate inferences about population-level processes. Here I discuss and review several lines of evidence that, I believe, best illustrate and summarize the limitations of inferences generated using non-natural model systems.

scholarly journals Influence of Calcium Binding on Conformations and Motions of Anionic Polyamino Acids. Effect of Side Chain Length

Polymers ◽  
2020 ◽  
Vol 12 (6) ◽  
pp. 1279
Author(s):  
Dmitry Tolmachev ◽  
Natalia Lukasheva ◽  
George Mamistvalov ◽  
Mikko Karttunen
Keyword(s):  
Amino Acids ◽  
Chain Length ◽  
Calcium Binding ◽  
Md Simulations ◽  
Side Chain ◽  
Replica Exchange ◽  
Side Chain Length ◽  
Hamiltonian Replica Exchange ◽  
Cacl2 Concentration ◽  
Chain Lengths

Investigation of the effect of CaCl2 salt on conformations of two anionic poly(amino acids) with different side chain lengths, poly-(α-l glutamic acid) (PGA) and poly-(α-l aspartic acid) (PASA), was performed by atomistic molecular dynamics (MD) simulations. The simulations were performed using both unbiased MD and the Hamiltonian replica exchange (HRE) method. The results show that at low CaCl2 concentration adsorption of Ca2+ ions lead to a significant chain size reduction for both PGA and PASA. With the increase in concentration, the chains sizes partially recover due to electrostatic repulsion between the adsorbed Ca2+ ions. Here, the side chain length becomes important. Due to the longer side chain and its ability to distance the charged groups with adsorbed ions from both each other and the backbone, PGA remains longer in the collapsed state as the CaCl2 concentration is increased. The analysis of the distribution of the mineral ions suggests that both poly(amino acids) should induce the formation of mineral with the same structure of the crystal cell.

scholarly journals Endophytic Actinomycetes: A Novel Source of Potential Acyl Homoserine Lactone Degrading Enzymes

2013 ◽  
Vol 2013 ◽  
pp. 1-8 ◽  
Author(s):  
Surang Chankhamhaengdecha ◽  
Suphatra Hongvijit ◽  
Akkaraphol Srichaisupakit ◽  
Pattra Charnchai ◽  
Watanalai Panbangred
Keyword(s):  
Pathogenic Bacteria ◽  
Sequence Similarity ◽  
Soft Rot ◽  
Quorum Quenching ◽  
Homoserine Lactone ◽  
Amide Bond ◽  
Side Chain ◽  
Signal Molecules ◽  
Endophytic Actinomycetes

Several Gram-negative pathogenic bacteria employN-acyl-L-homoserine lactone (HSL) quorum sensing (QS) system to control their virulence traits. Degradation of acyl-HSL signal molecules by quorum quenching enzyme (QQE) results in a loss of pathogenicity in QS-dependent organisms. The QQE activity of actinomycetes in rhizospheric soil and inside plant tissue was explored in order to obtain novel strains with high HSL-degrading activity. Among 344 rhizospheric and 132 endophytic isolates, 127 (36.9%) and 68 (51.5%) of them, respectively, possessed the QQE activity. The highest HSL-degrading activity was at151.30±3.1 nmole/h/mL from an endophytic actinomycetes isolate, LPC029. The isolate was identified asStreptomycesbased on16S  rRNAgene sequence similarity. The QQE from LPC029 revealed HSL-acylase activity that was able to cleave an amide bond of acyl-side chain in HSL substrate as determined by HPLC. LPC029 HSL-acylase showed broad substrate specificity from C6- to C12-HSL in which C10HSL is the most favorable substrate for this enzyme. In anin vitropathogenicity assay, the partially purified HSL-acylase efficiently suppressed soft rot of potato caused byPectobacterium carotovorumssp.carotovorumas demonstrated. To our knowledge, this is the first report of HSL-acylase activity derived from an endophyticStreptomyces.

scholarly journals Molecular dynamics simulations of the self-organization of side-chain decorated polyaromatic conjugation molecules: phase separated lamellar and columnar structures and dispersion behaviors in toluene solvent

RSC Advances ◽  
2018 ◽  
Vol 8 (20) ◽  
pp. 11134-11144 ◽  
Author(s):  
Lanyan He ◽  
Pingmei Wang ◽  
Lipeng He ◽  
Zhou Qu ◽  
Jianhui Luo ◽  
...  
Keyword(s):  
Molecular Dynamics ◽  
Molecular Dynamics Simulations ◽  
Molecular Dynamic ◽  
Md Simulations ◽  
The Self ◽  
Self Organization ◽  
Side Chain ◽  
Dynamics Simulations

The self-organization of five model side-chain decorated polyaromatic asphaltene molecules with or without toluene solvent was investigated by means of molecular dynamic (MD) simulations.

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