Daryl R. Williams

Imperial College London

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Jerry Y. Y. Heng

Imperial College London

Ilich A. Ibarra

Universidad Nacional Autónoma de México

Luqman Hakim Mohd Azmi

Imperial College London

Bradley P. Ladewig

University of Luxembourg

Eva Martínez‐Ahumada

Universidad Nacional Autónoma de México

Vladimir Martis

Electro-Medical Measurement Systems (United Kingdom)

Elwin Hunter‐Sellars

Lawrence Livermore National Laboratory

Pavani Cherukupally

University of Toronto

Andrew R. Cossins

University of Liverpool

B.J. Briscoe

Imperial College London

Cooperative Institutions

Imperial College London

110

University of Liverpool

Universidad Nacional Autónoma de México

University of Iowa

Centre National de la Recherche Scientifique

University of Cambridge

Transnational Press London

University College London

University of Southampton

University of Copenhagen

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Advancements in Loop Cyclization Approaches for Enhanced Peptide Therapeutics for Targeting Protein–Protein Interactions

The Journal of Organic Chemistry (2024)

Lucia Lombardi Luke A. Granger Robin J. Shattock Daryl R. Williams

Protein-protein interactions (PPIs) are pivotal in regulating cellular functions and life processes, making them promising therapeutic targets in modern medicine. Despite their potential, developing PPI inhibitors poses significant challenges due to their large and shallow interfaces that complicate ligand binding. This study focuses on mimicking peptide loops as a strategy for PPI inhibition, utilizing synthetic peptide loops for replicating critical binding regions. This work explores turn-inducing elements and highlights the importance of proline in promoting favorable conformations for lactamization, yielding high-purity cyclic peptides. Notably, our one-pot method offers enhanced versatility and represents a robust strategy for efficient and selective macrolactamization, expanding the scope of peptide synthesis methodologies. This approach, validated through the synthesis of AAV capsid-derived loops, offers a robust platform for developing peptide-based therapeutics and highlights the potential of peptide macrocycles in overcoming PPI drug discovery challenges and advancing the development of new therapeutics.

10.1021/acs.joc.4c02178

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Citations (0)

Influence of Vapor Condensation on the Adhesion and Friction of Carbon−Carbon Nanocontacts

Langmuir (2001)

M.J. Adams B.J. Briscoe Justin Law Paul F. Luckham Daryl R. Williams

The adhesion and friction between two orthogonally arranged carbon fibers has been measured in undersaturated vapor pressures of decane, n-propanol, and water. An analysis, which is described, of the frictional data allowed the normal adhesive force under sliding conditions to be deduced. Contact angle measurements and adsorption studies showed that both decane and n-propanol wetted the fibers and also their vapors exhibited typical BET adsorption isotherms. It was also found that water did not wet these fibers and that the adsorption isotherm could not be described by the BET equation. Equilibrium thermodynamic theory predicts that the two wetting fluids should significantly attenuate the autoadhesion. The converse was observed and is ascribed to the actions of a combination of two factors. First, it is argued that the high contact pressures (ca.109 Pa) at the carbon interface, which were developed even under the adhesive loads alone, resulted in the adsorbates being excluded or displaced from the contact region. Second, the crack propagation velocity during the interfacial separation process was very fast relative to the rate of vapor transport and hence the rate of adsorption at the crack tip. A similar effect is observed with environmental stress cracking at high crack propagation velocities. An increase in the adhesion at high relative vapor pressures of the n-propanol and water is considered to correspond to the formation of capillary bridges. The rate at which this process occurs appears to be enhanced under sliding conditions due to an accumulation of the adsorbates in the moving contact. The capillary bridges formed in saturated decane vapor were highly unstable which may be related to the relatively weak adsorption characteristics.

Capillary condensation

Kelvin equation

Decane

Carbon fibers

10.1021/la0103719

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Citations (25)

Molecular interaction and partitioning in α-keratin using ¹ H NMR spin-lattice ( T ₁ ) relaxation times

Journal of The Royal Society Interface (2021)

Susannah Molisso Daryl R. Williams Oscar Ces Lucy J. Rowlands Jennifer Marsh

The interactions between small molecules and keratins are poorly understood. In this paper, a nuclear magnetic resonance method is presented to measure changes in the 1 H T 1 relaxation times of small molecules in human hair keratin to quantify their interaction with the fibre. Two populations of small-molecule compounds were identified with distinct relaxation times, demonstrating the partitioning of the compounds into different keratin environments. The changes in relaxation time for solvent in hair compared with bulk solvent were shown to be related to the molecular weight (MW) and the partition coefficient, LogP, of the solvent investigated. Compounds with low MWs and high hydrophilicities had greater reductions in their T 1 relaxation times and therefore experienced increased interactions with the hair fibre. The relative population sizes were also calculated. This is a significant step towards modelling the behaviour of small molecules in keratinous materials and other large insoluble fibrous proteins.

Lattice (music)

10.1098/rsif.2021.0698

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Citations (4)

Surface Energy Mapping of Modified Silica Using IGC Technique at Finite Dilution

ACS Omega (2020)

Yen Wan Ngeow Daryl R. Williams Andrew V. Chapman Jerry Y. Y. Heng

The reinforcing silica filler, which can be more than 40% of an elastomer composite, plays a key role to achieve the desired mechanical properties in elastomer vulcanizates. However, the highly hydrophilic nature of silica surface causes silica particle aggregation. It remained a challenge for many tire manufacturers when using silica-filled elastomer compounds. Here, the silica surface energy changes when the surface is modified with coupling or noncoupling silanes; coupling silanes can covalently bond the silica to the elastomers. The surface energy of silica was determined using inverse gas chromatography (IGC) at finite dilution (FD-IGC) and found to be reduced by up to 50% when the silica surface was silanized. The spatial distribution of silica aggregates within the tire matrix is determined by transmission electron microscopy (TEM) and a direct correlation between aggregate size (silica microdispersion) and work of cohesion from IGC is reported, highlighting surface energy and work of cohesion being excellent indicators of the degree of dispersion of silica aggregates.

Inverse gas chromatography

Silanes

Dilution

10.1021/acsomega.9b03920

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Citations (9)

Decolourisation of Metal-azo Dyes in Wastewaters by Sodium Peroxodisulphate: A Template for Experimental Investigations

The Open Environmental Research Journal (2023)

Philip C.W. Cheung Daryl R. Williams Donald W. Kirk P. J. Murphy Stephen Barton

Background: It has long been recognized that the presence of azo metal complex dyes and their non-complexed counterparts in wastewaters, which is due to their manufacturing and use in the textile industries, renders natural waterways intensely coloured, and is therefore aesthetically unacceptable. Azo dye moieties are also known to be precursors of human carcinogenicity. Objective: This work aimed at the decolourisation of metal-azo dyes present in wastewaters so that pollution of natural bodies of water can be prevented. Decolourisation is indicative of the destruction of the metal-ligand complex, allowing the retrieval of transition metal ions, which are also water contaminants. Fracturing of the azo bond itself minimizes the potential for the carcinogenicity of these dyes. Methods: Decolourisation is achieved by the oxidative action of free radicals furnished by Na 2 S 2 O 8 , the sodium salt of peroxodisulphuric acid (Marshall’s acid). Raman spectroscopy characterizes the dye (ligand) known as “Eriochrome Black T (EBT)” by a peak at 1425 cm -1 . Dismantling of its molecular structure by peroxodisulphate will lead to decolourisation accompanied by the collapse of the peak. Concomitantly, as EBT ligands fracture and cease to chelate, metallic ions are released, oxidized to a higher oxidation state, and precipitated as insoluble compounds in alkaline media. Results: The concentration of metallic ions in the aqueous phase has been found to be substantially reduced. The successfully treated dye solutions are mostly clear and colourless; their Beer-Lambert absorbances are in the range of 0.02 ≤ absorbance ≤ 0.05. The treatment of Ni(II), Co(II) and Fe(II)-EBT solutions is straightforward; the Cu(II) and Cr(III)-EBT solutions require additional treatment to be included in the above absorbance range. The Cr(III)-EBT is the least responsive to treatment. Fracturing of the azo bond is evinced by Raman Spectroscopy. Conclusion: A template to investigate the feasibility of decolourisation of metal-complex dye solutions is pioneered and recommended.

Efflorescence

10.2174/25902776-v16-e230216-2022-2

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Citations (1)

Improved adsorption reactions, kinetics and stability for model and therapeutic proteins immobilised on affinity resins

Adsorption (2019)

Sarah Hedberg Lane Brown Alireza Meghdadi Daryl R. Williams

Protein adsorption on solid state media is important for the industrial affinity chromatography of biotherapeutics and for preparing materials for self-interaction chromatography where fundamental protein solution thermodynamic properties are measured. The adsorption of three model proteins (lysozyme, catalase and BSA) and two antibodies (a monoclonal and a polyclonal antibody) have been investigated on commercial affinity chromatography media with different surface functionalities (Formyl, Tresyl and Amino). Both the extent of protein immobilised (mg protein/ml media) and the reaction kinetics are reported for a range of reaction conditions, including pH, differing buffers as well as the presence of secondary reactants (glutaraldehyde, sodium cyanoborohydride, EDC and NHS). Compared to the reaction conditions recommended by manufacturers as well as those reported in previous published work, significant increases in the extent of protein immobilisation and reaction kinetics are reported here. The addition of glutaraldehyde or sodium cyanoborohydride was found to be especially effective even when not directly needed for the adsorption to happen. For mAb and pIgG, immobilisation levels of 50 and 31 mg of protein/ml of resin respectively were achieved, which are 100% or more than previously reported. Enhanced levels were achieved for lysozyme of 120 mg/ml with very rapid reaction kinetics (< 1 h) with sodium cyanoborohydride. It can be concluded that specific chromatography resins with Tresyl activated support offered enhanced levels of protein immobilisation due to their ability to react to form amine or thio-ether linkages with proteins. Additionally, glutaraldehyde can result in higher immobilisation levels whilst it can also accelerate immobilisation reaction kinetics.

Sodium cyanoborohydride

Glutaraldehyde

Bovine serum albumin

Polyclonal antibodies

10.1007/s10450-019-00106-5

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Citations (2)

Selective Crystallization of Proteins Using Engineered Nanonucleants

Crystal Growth & Design (2012)

Umang V. Shah Daryl R. Williams Jerry Y. Y. Heng

This study reports for the first time a detailed experimental investigation of protein crystallization in engineered nanoconfined spaces with both controlled pore diameters and narrow pore size distributions. We propose a systematic approach for controlling the nucleation and crystallization of biological macromolecules based on a relationship between the protein radius of gyration (Rg) and specific pore diameter. A series of nanonucleants with ordered mesopores having narrow pore size distributions were prepared. The templates were tested for proteins ranging in molecular weight from 14 to 450 kDa. Well-formed protein crystals were obtained on only one of the five presented nanonucleants for all protein cases tested, highlighting the unique template selectivity exhibited by these nucleants. In addition, concanavalin A and catalase were both crystallized at ∼2 times lower supersaturation levels than previously reported by any known method. Our observations fully support theoretical studies that predict the enhanced thermodynamic stability of proteins in nanoconfined cavities, including specifically the importance of nucleant pore diameter with respect to protein radius of gyration. The nucleants described here could have major industrial applications for downstream separation and purification of biopharmaceuticals, as well as improved opportunities for the crystallization of complex proteins for structural determination.

Protein crystallization

Radius of gyration

Supersaturation

Gyration

10.1021/cg201443s

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Citations (51)

A New Method To Determine Dispersive Surface Energy Site Distributions by Inverse Gas Chromatography

Langmuir (2014)

Robert R. Smith Daryl R. Williams Daniel J. Burnett Jerry Y. Y. Heng

A computational model to predict the relative energy site contributions of a heterogeneous material from data collected by finite dilution-inverse gas chromatography (FD-IGC) is presented in this work. The methodology employed a multisolvent system site filling model utilizing Boltzmann statistics, expanding on previous efforts to calculate "experienced energies" at varying coverage, yielding a retention volume distribution allowing calculation of a surface free energy distribution. Surface free energy distributions were experimentally measured for racemic ibuprofen and β-mannitol powders, the energies of each were found in the ranges 43-52 and 40-55 mJ/m(2), respectively, over a surface coverage range of 0-8%. The computed contributions to surface energy values were found to match closely with data collected on macroscopic crystals by alternative techniques (±<1.5 mJ/m(2)).

Inverse gas chromatography

10.1021/la500688d

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Citations (30)

Functionalized NU-1000 with an Iridium Organometallic Fragment: SO₂ Capture Enhancement

ACS Applied Materials & Interfaces (2020)

Saidulu Gorla Mariana L. Díaz‐Ramírez Niroshani S. Abeynayake David M. Kaphan Daryl R. Williams

A new material, MOF-type [Ir]@NU-1000, was accessed from the incorporation of the iridium organometallic fragment [Ir{κ3(P,Si,Si)PhP(o-C6H4CH2SiiPr2)2}] into NU-1000. The new material incorporates less than 1 wt % of Ir(III) (molar ratio Ir to NU-1000, 1:11), but the heat of adsorption for SO2 is significantly enhanced with respect to that of NU-1000. Being a highly promising adsorbent for SO2 capture, [Ir]@NU-1000 combines exceptional SO2 uptake at room temperature and outstanding cyclability. Additionally, it is stable and can be regenerated after SO2 desorption at low temperature.

Fragment (logic)

Molar ratio

10.1021/acsami.0c11615

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Citations (29)

Cross-interaction chromatography as a rapid screening technique to identify the stability of new antibody therapeutics

European Journal of Pharmaceutics and Biopharmaceutics (2018)

Sarah Hedberg Jonathan Rapley Jonathan Haigh Daryl R. Williams

Polyclonal antibodies

Process development

10.1016/j.ejpb.2018.10.009

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Citations (10)