PepSeA: Peptide Sequence Alignment and Visualization Tools to Enable Lead Optimization

Therapeutic peptides offer potential advantages over small molecules in terms of selectivity, affinity, and their ability to target "undruggable" proteins that are associated with a wide range of pathologies. Despite their importance, there are currently no adequate molecular design capabilities that inform medicinal chemistry decisions on peptide programs. More specifically, SAR (Structure-Activity Relationship) analysis and visualization of linear, cyclic, and cross-linked peptides containing non-natural motifs, which are widely used in drug discovery. To bridge this gap, we developed PepSeA (Peptide Sequence Alignment and Visualization), an open-source, freely available package of sequence-based tools (https://github.com/Merck/PepSeA). PepSeA enables multi-sequence alignment of non-natural amino acids and enhanced HELM (Hierarchical Editing Language for Macromolecules) visualization. Via stepwise SAR analysis of a ChEMBL peptide dataset, we demonstrate PepSeA's power to accelerate decision making in lead optimization campaigns in pharmaceutical settings. PepSeA represents an initial attempt to expand cheminformatics capabilities for therapeutic peptides and to enable rapid and more efficient design-make-test cycles.

Download Full-text

Engineering the Interface between Inorganic Nanoparticles and Biological Systems through Ligand Design

Nanomaterials ◽

10.3390/nano11041001 ◽

2021 ◽

Vol 11 (4) ◽

pp. 1001

Author(s):

Rui Huang ◽

David C. Luther ◽

Xianzhi Zhang ◽

Aarohi Gupta ◽

Samantha A. Tufts ◽

...

Keyword(s):

Organic Synthesis ◽

Molecular Design ◽

Biological Systems ◽

Ligand Design ◽

Inorganic Nanoparticles ◽

Organic Ligands ◽

Biological Applications ◽

Wide Range ◽

Insight Into

Nanoparticles (NPs) provide multipurpose platforms for a wide range of biological applications. These applications are enabled through molecular design of surface coverages, modulating NP interactions with biosystems. In this review, we highlight approaches to functionalize nanoparticles with ”small” organic ligands (Mw < 1000), providing insight into how organic synthesis can be used to engineer NPs for nanobiology and nanomedicine.

Download Full-text

Fast in-situ X-ray scattering reveals stress sensitivity of gypsum dehydration kinetics

Communications Materials ◽

10.1038/s43246-021-00156-9 ◽

2021 ◽

Vol 2 (1) ◽

Author(s):

Christoph Eckart Schrank ◽

Oliver Gaede ◽

Tomasz Blach ◽

Katherine Carmen Michelle Gioseffi ◽

Stephen Mudie ◽

...

Keyword(s):

Stress Sensitivity ◽

Water Vapour Pressure ◽

Fast Time ◽

Dehydration Kinetics ◽

Efficient Design ◽

X Ray ◽

Triggered Earthquakes ◽

X Ray Scattering ◽

Wide Range ◽

Ray Scattering

AbstractThe dehydration of gypsum to hemihydrate has been studied for decades because it is an important model reaction for understanding fluid-triggered earthquakes, and due to the global use of plaster of Paris in the construction industry. The dehydration kinetics of gypsum strongly depend on temperature and water vapour pressure. Here, we perform fast, time-resolved synchrotron X-ray scattering on natural alabaster samples, finding that a small elastic load accelerates the dehydration reaction significantly. The mechanical acceleration of the reaction consumes about 10,000 times less energy than that due to heating. We propose that this thermodynamically surprising finding is caused by geometry-energy interactions in the microstructure, which facilitate nucleation and growth of the new crystalline phase. Our results open research avenues on the fundamental thermo-mechanics of crystal hydrates and the interaction of stress and chemical reactions in crystalline solids with a wide range of implications, from understanding dehydration-triggered earthquakes to the energy-efficient design of calcination processes.

Download Full-text

Efficient Design of Micro Strip Patch Antenna for the Ultra Wideband (UWB) Applications

International Journal of Recent Technology and Engineering - 2 ◽

10.35940/ijrte.e6822.018520 ◽

2020 ◽

Vol 8 (5) ◽

pp. 4517-4520

Keyword(s):

Patch Antenna ◽

Wide Band ◽

Ultra Wideband ◽

Ultra Wide Band ◽

Strip Line ◽

Efficient Design ◽

Uwb Antennas ◽

Feeding Technique ◽

Wide Range ◽

Uwb Applications

In this research paper a design of Microstip patch antenna for the ultra-wide band (UWB) applications is presented. Ultra wide band antennas has very wide band of operation which accommodates many communication frequencies as set by the federal commission of communication. The UWB antennas is based on the micro strip patch antenna concept and the design of the antenna is based on the stack antenna or multi-layer antenna. Stacking is used in designing for increasing the bandwidth of the antenna so stacking concept is good for the designing of the UWB antenna. The feeding used to feed the antenna is micro strip line feed. Micro strip line feeding technique is one of very popular feeding technique to feed the antenna because its fabrication is very simple. The proposed design is simulated in the CADFEKO software which is very useful for the design and analysis of a wide range of electromagnetic problem. It has many applications to simulate 3D electromagnetic circuit included antenna design, micro strip antenna and circuits. The simulation results shows the antenna bandwidth of 13.9 GHz from 2.6 to 16.5 GHz. So we can clearly say that the antenna is ultra-wide band in nature.

Download Full-text

HemoNet: Predicting hemolytic activity of peptides with integrated feature learning

Journal of Bioinformatics and Computational Biology ◽

10.1142/s0219720021500219 ◽

2021 ◽

pp. 2150021

Author(s):

Adiba Yaseen ◽

Sadaf Gull ◽

Naeem Akhtar ◽

Imran Amin ◽

Fayyaz Minhas

Keyword(s):

Amino Acids ◽

Hemolytic Activity ◽

Cross Validation ◽

Feature Learning ◽

Predictive Performance ◽

Peptide Sequence ◽

Therapeutic Peptides ◽

Wet Lab ◽

Novel Therapeutic

Quantifying the hemolytic activity of peptides is a crucial step in the discovery of novel therapeutic peptides. Computational methods are attractive in this domain due to their ability to guide wet-lab experimental discovery or screening of peptides based on their hemolytic activity. However, existing methods are unable to accurately model various important aspects of this predictive problem such as the role of N/C-terminal modifications, D- and L- amino acids, etc. In this work, we have developed a novel neural network-based approach called HemoNet for predicting the hemolytic activity of peptides. The proposed method captures the contextual importance of different amino acids in a given peptide sequence using a specialized feature embedding in conjunction with SMILES-based fingerprint representation of N/C-terminal modifications. We have analyzed the predictive performance of the proposed method using stratified cross-validation in comparison with previous methods, non-redundant cross-validation as well as validation on external peptides and clinical antimicrobial peptides. Our analysis shows the proposed approach achieves significantly better predictive performance (AUC-ROC of 88%) in comparison to previous approaches (HemoPI and HemoPred with AUC-ROC of 73%). HemoNet can be a useful tool in the search for novel therapeutic peptides. The python implementation of the proposed method is available at the URL: https://github.com/adibayaseen/HemoNet.

Download Full-text

Molecular Design of Environmentally Adapted Lubricants: Antiwear Additives Derived from Natural Amino Acids

Tribology Transactions ◽

10.1080/10402001003728897 ◽

2010 ◽

Vol 53 (5) ◽

pp. 713-721 ◽

Cited By ~ 21

Author(s):

Ichiro Minami ◽

Shigeyuki Mori ◽

Yukihiro Isogai ◽

Satoshi Hiyoshi ◽

Toshihiro Inayama ◽

...

Keyword(s):

Amino Acids ◽

Molecular Design ◽

Antiwear Additives ◽

Natural Amino Acids

Download Full-text

Identification, Characterization, and Recombinant Expression of Epidermicin NI01, a Novel Unmodified Bacteriocin Produced by Staphylococcus epidermidis That Displays Potent Activity against Staphylococci

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.05397-11 ◽

2011 ◽

Vol 56 (3) ◽

pp. 1539-1547 ◽

Cited By ~ 61

Author(s):

Stephanie Sandiford ◽

Mathew Upton

Keyword(s):

Antimicrobial Activity ◽

Structural Gene ◽

Staphylococcus Epidermidis ◽

De Novo ◽

Sequence Data ◽

Recombinant Expression ◽

Draft Genome ◽

Peptide Sequence ◽

Content Type ◽

Wide Range

ABSTRACTWe describe the discovery, purification, characterization, and expression of an antimicrobial peptide, epidermicin NI01, which is an unmodified bacteriocin produced byStaphylococcus epidermidisstrain 224. It is a highly cationic, hydrophobic, plasmid-encoded peptide that exhibits potent antimicrobial activity toward a wide range of pathogenic Gram-positive bacteria including methicillin-resistantStaphylococcus aureus(MRSA), enterococci, and biofilm-formingS. epidermidisstrains. Purification of the peptide was achieved using a combination of hydrophobic interaction, cation exchange, and high-performance liquid chromatography (HPLC). Matrix-assisted laser desorption ionization–time of flight (MALDI-TOF) analysis yielded a molecular mass of 6,074 Da, and partial sequence data of the peptide were elucidated using a combination of tandem mass spectrometry (MS/MS) andde novosequencing. The draft genome sequence of the producing strain was obtained using 454 pyrosequencing technology, thus enabling the identification of the structural gene using thede novopeptide sequence data previously obtained. Epidermicin NI01 contains 51 residues with four tryptophan and nine lysine residues, and the sequence showed approximately 50% identity to peptides lacticin Z, lacticin Q, and aureocin A53, all of which belong to a new family of unmodified type II-like bacteriocins. The peptide is active in the nanomolar range againstS. epidermidis, MRSA isolates, and vancomycin-resistant enterococci. Other unique features displayed by epidermicin include a high degree of protease stability and the ability to retain antimicrobial activity over a pH range of 2 to 10, and exposure to the peptide does not result in development of resistance in susceptible isolates. In this study we also show the structural gene alone can be cloned intoEscherichia colistrain BL21(DE3), and expression yields active peptide.

Download Full-text

Expression of the Ghrelin Axis in the Mouse: An Exon 4-Deleted Mouse Proghrelin Variant Encodes a Novel C Terminal Peptide

Endocrinology ◽

10.1210/en.2003-1466 ◽

2005 ◽

Vol 146 (1) ◽

pp. 432-440 ◽

Cited By ~ 31

Author(s):

P. L. Jeffery ◽

R. P. Duncan ◽

A. H. Yeh ◽

R. A. Jaskolski ◽

D. S. Hammond ◽

...

Keyword(s):

Mrna Expression ◽

Tissue Expression ◽

Peptide Sequence ◽

Amino Acid Peptide ◽

Gh Secretion ◽

Mrna Variant ◽

Mouse Tissues ◽

Wide Range ◽

Ghrelin Gene ◽

Exon 4

Ghrelin, an n-octanoylated 28-amino-acid peptide capable of inducing GH secretion and food intake in humans and rats, is the endogenous ligand for the GH secretagogue receptor (GHS-R). Here we describe the expression and tissue distribution of the ghrelin/GHS-R axis in the mouse. We also report for the first time the identification of a novel mouse ghrelin mRNA variant in which there is a complete deletion of exon 4. Translation of this variant mRNA yields a protein containing ghrelin and an alternative C-terminal domain with a unique C-terminal peptide sequence. RT-PCR with primers specific for mouse ghrelin was used to demonstrate the mRNA expression of the full preproghrelin transcript and the exon 4-deleted variant in multiple mouse tissues. Real-time PCR was also employed to quantitate mRNA expression of ghrelin, the novel isoform and a previously reported ghrelin gene variant, ghrelin gene-derived transcript. We also demonstrated the tissue expression of the functional GHS-R in the mouse. Immunohistochemistry, employing antibodies raised against the mature human n-octanoylated ghrelin peptide and the putative C-terminal peptide encoded by the exon 4-deleted proghrelin variant, was used to demonstrate protein expression of ghrelin and the variant in multiple mouse tissues including stomach, kidney, and reproductive tissues. The coexpression of ghrelin and its receptor in a wide range of murine tissues suggests varied autocrine/paracrine roles for these peptides. Exon 4-deleted proghrelin, a novel mouse proghrelin isoform with a unique C-terminal peptide sequence, is also widely expressed in the mouse and thus may possess biological activity in these tissues.

Download Full-text

Co-assembly of helical β3-peptides: a self-assembled analogue of a statistical copolymer

Pure and Applied Chemistry ◽

10.1515/pac-2017-0709 ◽

2017 ◽

Vol 89 (12) ◽

pp. 1809-1816 ◽

Cited By ~ 2

Author(s):

Claire Buchanan ◽

Christopher J. Garvey ◽

Patrick Perlmutter ◽

Adam Mechler

Keyword(s):

Amino Acids ◽

Physical Properties ◽

Self Assembly ◽

Unnatural Amino Acids ◽

The Self ◽

Microscopy Imaging ◽

Wide Range ◽

Self Assembled ◽

Unnatural Peptides ◽

Natural Amino Acids

AbstractUnnatural peptide self-assembly offers the means to design hierarchical nanostructures of controlled geometries, chemical function and physical properties. N-acyl β3 peptides, where all residues are unnatural amino acids, are able to form helical fibrous structures by a head-to-tail assembly of helical monomers, extending the helix via a three point supramolecular hydrogen bonding motif. These helical nanorods were shown to be stable under a wide range of physical conditions, offering a self-assembled analogue of polymeric fibres. Hitherto the self-assembly has only been demonstrated between identical monomers; however the self-assembly motif is sequence-independent, offering the possibility of hetero-assembly of different peptide monomers. Here we present a proof of principle study of head-to-tail co-assembly of two different helical unnatural peptides Ac-β3[WELWEL] and Ac-β3[LIA], where the letters denote the β3 analogues of natural amino acids. By atomic force microscopy imaging it was demonstrated that the homo-assembly and co-assembly of these peptides yield characteristically different structures. Synchrotron small angle X-ray scattering experiments have confirmed the presence of the fibres in the solution and the averaged diameters from modelled data correlate well to the results of AFM imaging. Hence, there is evidence of co-assembly of the fibrous superstructures; given that different monomers may be used to introduce variations into chemical and physical properties, the results demonstrate a self-assembled analogue of a statistical co-polymer that can be used in designing complex functional nanomaterials.

Download Full-text

Computational modeling of UV photocatalytic reactors: model development, evaluation, and application

Water Quality Research Journal ◽

10.2166/wqrjc.2014.031 ◽

2014 ◽

Vol 50 (1) ◽

pp. 21-33 ◽

Cited By ~ 1

Author(s):

J. Esteban Duran ◽

Madjid Mohseni ◽

Fariborz Taghipour

Keyword(s):

Design Optimization ◽

Reactor Design ◽

Base Case ◽

Emission Model ◽

Hydrodynamic Conditions ◽

Efficient Design ◽

Chemical Reaction Kinetics ◽

Taguchi Design Of Experiments ◽

Wide Range ◽

Uv Lamp

A computational model for simulating the performance of immobilized photocatalytic ultraviolet (UV) reactors used for water treatment was developed, experimentally evaluated, and applied to reactor design optimization. This model integrated hydrodynamics, species mass transport, chemical reaction kinetics, and irradiance distribution within the reactor. Among different hydrodynamic models evaluated against experimental data, the laminar, Abe–Kondoh–Nagano, and Reynolds stress turbulence models showed better performance (errors <5%, 12%, and 20%, respectively) in terms of external mass transfer and surface reaction prediction capabilities at different hydrodynamic conditions. A developed finite-volume-based UV lamp emission model was able to predict, with errors of less than 5%, near- and far-field irradiance measurements. Combining all these models, the integrated computational fluid dynamics (CFD)-based model was able to successfully predict the photocatalytic degradation rate of model pollutants (benzoic acid and 2,4-D) in various configurations of annular reactors and UV lamp sizes, over a wide range of hydrodynamic conditions (350 < Re < 11,000). In addition, the integrated model was used in combination with a Taguchi design of experiments method to perform reactor design optimization. Following this approach, a base case annular reactor design was modified to obtain a 50% more efficient design.

Download Full-text

Identification and characterization of the cytosine-5 DNA methyltransferase gene family in Salvia miltiorrhiza

PeerJ ◽

10.7717/peerj.4461 ◽

2018 ◽

Vol 6 ◽

pp. e4461 ◽

Cited By ~ 3

Author(s):

Jiang Li ◽

Caili Li ◽

Shanfa Lu

Keyword(s):

Dna Methylation ◽

Salicylic Acid ◽

Gene Family ◽

Sequence Alignment ◽

Dna Methyltransferase ◽

Epigenetic Modification ◽

Salvia Miltiorrhiza ◽

Dna Methyltransferases ◽

Genome Wide ◽

Wide Range

Cytosine DNA methylation is highly conserved epigenetic modification involved in a wide range of biological processes in eukaryotes. It was established and maintained by cytosine-5 DNA methyltransferases (C5-MTases) in plants. Through genome-wide identification, eight putative SmC5-MTase genes were identified from the genome of Salvia miltiorrhiza, a well-known traditional Chinese medicine material and an emerging model medicinal plant. Based on conserved domains and phylogenetic analysis, eight SmC5-MTase genes were divided into four subfamilies, including MET, CMT, DRM and DNMT2. Genome-wide comparative analysis of the C5-MTase gene family in S. miltiorrhiza and Arabidopsis thaliana, including gene structure, sequence features, sequence alignment and conserved motifs, was carried out. The results showed conservation and divergence of the members of each subfamily in plants. The length of SmC5-MTase open reading frames ranges widely from 1,152 (SmDNMT2) to 5,034 bp (SmMET1). The intron number of SmC5-MTases varies between 7 (SmDRM1) and 20 (SmCMT1 and SmCMT2b). These features were similar to their counterparts from Arabidopsis. Sequence alignment and conserved motif analysis showed the existence of highly conserved and subfamily-specific motifs in the C5-MTases analyzed. Differential transcript abundance was detected for SmC5-MTases, implying genome-wide variance of DNA methylation in different organs and tissues. Transcriptome-wide analysis showed that the transcript levels of all SmC5-MTase genes was slightly changed under yeast extract and methyl jasmonate treatments. Six SmC5-MTases, including SmMET1, SmCMT1, SmCMT2a, SmCMT2b, SmCMT3 and SmDRM1, were salicylic acid-responsive, suggesting the involvement of SmC5-MTases in salicylic acid-dependent immunity. These results provide useful information for demonstrating the role of DNA methylation in bioactive compound biosynthesis and Dao-di herb formation in medicinal plants.

Download Full-text