scholarly journals De novo rational design of a freestanding, supercharged polypeptide, proton-conducting membrane

2020 ◽  
Vol 6 (29) ◽  
pp. eabc0810 ◽  
Author(s):  
Chao Ma ◽  
Jingjin Dong ◽  
Marco Viviani ◽  
Isotta Tulini ◽  
Nicola Pontillo ◽  
...  
Keyword(s):  
Carboxylic Acid ◽  
Rational Design ◽  
De Novo ◽  
Proton Translocation ◽  
Proton Conduction ◽  
Device Fabrication ◽  
Proton Conducting ◽  
Intrinsically Disordered ◽  
Design Paradigm ◽  
Β Sheet

Proton translocation enables important processes in nature and man-made technologies. However, controlling proton conduction and fabrication of devices exploiting biomaterials remains a challenge. Even more difficult is the design of protein-based bulk materials without any functional starting scaffold for further optimization. Here, we show the rational design of proton-conducting, protein materials exceeding reported proteinaceous systems. The carboxylic acid–rich structures were evolved step by step by exploring various sequences from intrinsically disordered coils over supercharged nanobarrels to hierarchically spider β sheet containing protein-supercharged polypeptide chimeras. The latter material is characterized by interconnected β sheet nanodomains decorated on their surface by carboxylic acid groups, forming self-supportive membranes and allowing for proton conduction in the hydrated state. The membranes showed an extraordinary proton conductivity of 18.5 ± 5 mS/cm at RH = 90%, one magnitude higher than other protein devices. This design paradigm offers great potential for bioprotonic device fabrication interfacing artificial and biological systems.

scholarly journals Theoretical hydrogen bonding calculations and proton conduction for Eu(iii)-based metal–organic framework

RSC Advances ◽  
2021 ◽  
Vol 11 (19) ◽  
pp. 11495-11499
Author(s):  
Lu Feng ◽  
Tian-Yu Zeng ◽  
Hao-Bo Hou ◽  
Hong Zhou ◽  
Jian Tian
Keyword(s):  
Hydrogen Bonding ◽  
Theoretical Calculation ◽  
Proton Transport ◽  
Metal Organic Framework ◽  
Proton Conduction ◽  
Transport Channel ◽  
Proton Conducting ◽  
Metal Organic ◽  
Organic Framework

A water-mediated proton-conducting Eu(iii)-MOF has been synthesized, which provides a stable proton transport channel that was confirmed by theoretical calculation.

scholarly journals Binding Ensembles of p53-MDM2 Peptide Inhibitors by Combining Bayesian Inference and Atomistic Simulations

Molecules ◽  
2021 ◽  
Vol 26 (1) ◽  
pp. 198
Author(s):  
Lijun Lang ◽  
Alberto Perez
Keyword(s):  
Bayesian Inference ◽  
Virtual Screening ◽  
Statistical Mechanics ◽  
Small Molecules ◽  
Rational Design ◽  
Driving Forces ◽  
Peptide Inhibitors ◽  
Atomistic Simulations ◽  
Binding Mechanism ◽  
Intrinsically Disordered

Designing peptide inhibitors of the p53-MDM2 interaction against cancer is of wide interest. Computational modeling and virtual screening are a well established step in the rational design of small molecules. But they face challenges for binding flexible peptide molecules that fold upon binding. We look at the ability of five different peptides, three of which are intrinsically disordered, to bind to MDM2 with a new Bayesian inference approach (MELD × MD). The method is able to capture the folding upon binding mechanism and differentiate binding preferences between the five peptides. Processing the ensembles with statistical mechanics tools depicts the most likely bound conformations and hints at differences in the binding mechanism. Finally, the study shows the importance of capturing two driving forces to binding in this system: the ability of peptides to adopt bound conformations (ΔGconformation) and the interaction between interface residues (ΔGinteraction).

scholarly journals Computer-Based Redesign of a β Sandwich Protein Suggests that Extensive Negative Design Is Not Required for De Novo β Sheet Design

Structure ◽  
2008 ◽  
Vol 16 (12) ◽  
pp. 1799-1805 ◽  
Author(s):  
Xiaozhen Hu ◽  
Huanchen Wang ◽  
Hengming Ke ◽  
Brian Kuhlman
Keyword(s):  
De Novo ◽  
Computer Based ◽  
Β Sheet

Electrochemical oxidation of 5-hydroxymethylfurfural on ternary metal-organic frameworks nanoarrays: enhancement from electronic structure modulation

2021 ◽  
Author(s):  
Xiaojue Bai ◽  
Wenxiu He ◽  
Xingyu Lu ◽  
Yu Fu ◽  
Wei Qi
Keyword(s):  
Electronic Structure ◽  
Carboxylic Acid ◽  
Electrochemical Oxidation ◽  
Rational Design ◽  
Metal Organic Frameworks ◽  
Highly Active ◽  
Ternary Metal ◽  
Metal Organic ◽  
Structure Modulation

The rational design and exploitation of highly active and stable catalysts for the electrochemical oxidation of biomass-derived 5-hydroxymethylfurfural (HMF) to valuable chemical 2,5-furandi-carboxylic acid (FDCA), is of great significance. Herein,...

scholarly journals An antibody that prevents serpin polymerisation acts by inducing a novel allosteric behaviour

2016 ◽  
Vol 473 (19) ◽  
pp. 3269-3290 ◽  
Author(s):  
Neda Motamedi-Shad ◽  
Alistair M. Jagger ◽  
Maximilian Liedtke ◽  
Sarah V. Faull ◽  
Arjun Scott Nanda ◽  
...  
Keyword(s):  
Rational Design ◽  
Conformational Transition ◽  
Structural Basis ◽  
Linear Polymers ◽  
Single Chain ◽  
Opposite Face ◽  
Induced Changes ◽  
Β Sheet ◽  
Chain Form ◽  
Antiprotease Activity

Serpins are important regulators of proteolytic pathways with an antiprotease activity that involves a conformational transition from a metastable to a hyperstable state. Certain mutations permit the transition to occur in the absence of a protease; when associated with an intermolecular interaction, this yields linear polymers of hyperstable serpin molecules, which accumulate at the site of synthesis. This is the basis of many pathologies termed the serpinopathies. We have previously identified a monoclonal antibody (mAb4B12) that, in single-chain form, blocks α1-antitrypsin (α1-AT) polymerisation in cells. Here, we describe the structural basis for this activity. The mAb4B12 epitope was found to encompass residues Glu32, Glu39 and His43 on helix A and Leu306 on helix I. This is not a region typically associated with the serpin mechanism of conformational change, and correspondingly the epitope was present in all tested structural forms of the protein. Antibody binding rendered β-sheet A — on the opposite face of the molecule — more liable to adopt an ‘open’ state, mediated by changes distal to the breach region and proximal to helix F. The allosteric propagation of induced changes through the molecule was evidenced by an increased rate of peptide incorporation and destabilisation of a preformed serpin–enzyme complex following mAb4B12 binding. These data suggest that prematurely shifting the β-sheet A equilibrium towards the ‘open’ state out of sequence with other changes suppresses polymer formation. This work identifies a region potentially exploitable for a rational design of ligands that is able to dynamically influence α1-AT polymerisation.

scholarly journals Surface Engineering of Top7 to Facilitate Structure Determination

2022 ◽  
Vol 23 (2) ◽  
pp. 701
Author(s):  
Yuki Ito ◽  
Takuya Araki ◽  
Shota Shiga ◽  
Hiroyuki Konno ◽  
Koki Makabe
Keyword(s):  
Structure Determination ◽  
Surface Engineering ◽  
De Novo ◽  
Crystal Packing ◽  
Structure Model ◽  
X Ray ◽  
Hexahistidine Tag ◽  
Model Protein ◽  
Β Sheet ◽  
Packing Interactions

Top7 is a de novo designed protein whose amino acid sequence has no evolutional trace. Such a property makes Top7 a suitable scaffold for studying the pure nature of protein and protein engineering applications. To use Top7 as an engineering scaffold, we initially attempted structure determination and found that crystals of our construct, which lacked the terminal hexahistidine tag, showed weak diffraction in X-ray structure determination. Thus, we decided to introduce surface residue mutations to facilitate crystal structure determination. The resulting surface mutants, Top7sm1 and Top7sm2, crystallized easily and diffracted to the resolution around 1.7 Å. Despite the improved data, we could not finalize the structures due to high R values. Although we could not identify the origin of the high R values of the surface mutants, we found that all the structures shared common packing architecture with consecutive intermolecular β-sheet formation aligned in one direction. Thus, we mutated the intermolecular interface to disrupt the intermolecular β-sheet formation, expecting to form a new crystal packing. The resulting mutant, Top7sm2-I68R, formed new crystal packing interactions as intended and diffracted to the resolution of 1.4 Å. The surface mutations contributed to crystal packing and high resolution. We finalized the structure model with the R/Rfree values of 0.20/0.24. Top7sm2-I68R can be a useful model protein due to its convenient structure determination.

scholarly journals De Novo Protein Design of Photochemical Reaction Centers

2021 ◽  
Author(s):  
Nathan Ennist ◽  
Zhenyu Zhao ◽  
Steven Stayrook ◽  
Bohdana Discher ◽  
P Leslie 'Les' Dutton ◽  
...  
Keyword(s):  
Reaction Center ◽  
Charge Separation ◽  
Rational Design ◽  
De Novo ◽  
Metal Cluster ◽  
Protein Structures ◽  
Essential Elements ◽  
Reaction Centers ◽  
Transient Absorption Spectroscopy

Abstract Natural photosynthetic protein complexes capture sunlight to power the energetic catalysis that supports life on Earth. Yet these natural protein structures carry an evolutionary legacy of complexity and fragility that encumbers protein reengineering efforts and obfuscates the underlying design rules for light-driven charge separation. De novo development of a simplified photosynthetic reaction center protein can clarify practical engineering principles needed to build new enzymes for efficient solar-to-fuel energy conversion. Here we report the rational design, X-ray crystal structure, and electron transfer activity of a multi-cofactor protein that incorporates essential elements of photosynthetic reaction centers. This highly stable, modular artificial protein framework can be reconstituted in vitro with interchangeable redox centers for nanometer-scale photochemical charge separation. Transient absorption spectroscopy demonstrates Photosystem II-like tyrosine and metal cluster oxidation, and we measure charge separation lifetimes exceeding 100 ms, ideal for light-activated catalysis. This de novo-designed reaction center builds upon engineering guidelines established for charge separation in earlier synthetic photochemical triads and modified natural proteins, and it shows how synthetic biology may lead to a new generation of genetically encoded, light-powered catalysts for solar fuel production.

scholarly journals Catechol-Containing Compounds are a Broad Class of Protein Aggregation Inhibitors: Redox State is a Key Determinant of the Inhibitory Activities

2020 ◽  
Author(s):  
Paul Velander ◽  
Ling Wu ◽  
Sherry B. Hildreth ◽  
Nancy J. Vogelaar ◽  
Biswarup Mukhopadhyay ◽  
...  
Keyword(s):  
Protein Aggregation ◽  
Small Molecule ◽  
Rational Design ◽  
Redox State ◽  
Broad Class ◽  
Intrinsically Disordered ◽  
Amyloidogenic Proteins ◽  
Key Factor ◽  
Inhibitory Activities ◽  
Screening Platform

Abstract Background: A range of neurodegenerative and related aging diseases, such as Alzheimer’s disease, Parkinson’s disease, and type 2 diabetes, are linked to toxic protein aggregation. Yet the mechanisms of protein aggregation inhibition by small molecule inhibitors remain poorly understood, in part because most protein targets of aggregation assembly are partially unfolded or intrinsically disordered, which hinders detailed structural characterization of protein-inhibitor complexes and structural-based mechanistic elucidation. Methods: Herein we employed a small molecule screening approach to identify inhibitors against three prototype amyloidogenic proteins in neurodegeneration and related proteinopathies: amylin, Ab and tau. We further systematically investigated selected class of inhibitors under aerobic and anaerobic conditions to uncover a key determinant of the inhibitory activities.Results: One remarkable class of inhibitors identified from all three parallel screenings against different amyloidogenic proteins was catechol-containing compounds and redox-related quinones/anthraquinones. Further mechanistic studies determined that the redox state of the broad class of catechol-containing compounds is a key determinant of the amyloid inhibitor activities. Conclusion: Our small molecule library screening platform was able to identify a broad class of amyloid inhibitors. Redox was found to be a key factor not only regulating the inhibitory activities but also involving the mechanism of inhibition. The molecular insights we gained not only explain why a large number of catechol-containing natural compounds, often enriched in healthy diet, have anti-neurodegeneration and anti-aging activities, but also could guide the rational design of therapeutic or nutraceutical strategies to target a broad range of neurodegenerative and related aging diseases.

scholarly journals Rational design of inducible CRISPR guide RNAs for de novo assembly of transcriptional programs

2017 ◽  
Vol 8 (1) ◽  
Author(s):  
Quentin R. V. Ferry ◽  
Radostina Lyutova ◽  
Tudor A. Fulga
Keyword(s):  
De Novo Assembly ◽  
Rational Design ◽  
De Novo ◽  
Guide Rnas
Sign in / Sign up

Export Citation Format

Share Document