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Single-Molecule Mechanoresistivity by Intermetallic Bonding
No full textThe metal-electrode interface is key to unlocking emergent behaviour in all organic electrified systems,
from battery technology to molecular electronics. In the latter, interfacial engineering has enabled
efficient transport, higher device stability, and novel functionality. Mechanoresistivity – the change in
electrical behaviour in response to a mechanical stimulus and a pathway to extremely sensitive force
sensors – is amongst the most studied phenomena in molecular electronics, and the molecule-electrode
interface plays a pivotal role in its emergence, reproducibility, and magnitude. In this contribution, we
show that organometallic molecular wires incorporating a Pt(II) cation show mechanoresistive
behaviour of exceptional magnitude, with conductance modulations of more than three orders of
magnitude upon compression by as little as 1 nm. We synthesised series of cyclometalated Pt(II)
molecular wires, and used scanning tunnelling microscopy – break junction techniques to characterise
their electromechanical behaviour. Mechanoresistivity arises from an interaction between the Pt(II)
cation and the Au electrode triggered by mechanical compression of the single-molecule device, and
theoretical modelling confirms this hypothesis. Our study provides a new tool for the design of functional
molecular wires by exploiting previously unreported ion-metal interactions in single-molecule devices,
and develops a new framework for the development of mechanoresistive molecular junctions
Investigation of the non-radiative photo-processes of unnatural DNA base: 7-(2-thienyl)-imidazo[4,5-b]pyridine (Ds) - A computational study
No full text7-(2-thienyl)-imidazo[4,5-b]pyridine (Ds) is an unnatural nucleic acid which forms stable pair with Pyrrole-2-carbaldehyde (Pa) in DNA. This Ds-Pa pair gets stabilized via van der Waals interaction and shape fitting. In our previous study,\cite{ghosh2021radiationless} we investigated the non-radiative photo-processes of unnatural DNA base Pa and also there are some studies on its stability and reactivity in the ground state. But to form a good unnatural base pair, one has to understand its stability not only in the ground state but also in the excited states after absorbing UV radiation. Therefore, in this study, the excited state photo-processes of Ds on UV irradiation and it\u27s non-radiative decay channels have been investigated. It is shown using state of the art multi reference methods and this investigation finally leads the molecule to access minimum energy crossing point (MECP) via a downhill pathway
Single molecule identification and quantification of whole proteins without purification, proteolysis, or labeling: a computational model
No full textA recent report shows that with a suitably designed buffer solution proteins can be unfolded and translocated through a nanopore unidirectionally and uniformly, with residues exiting the pore in sequence order at a roughly constant rate of 1/µs (Nature Biotechnology 41, 1130–1139, 2023). The present work shows in theory that by sampling the signal of pore exclusion volume (a proxy for the measured blockade current) at a low frequency of 10-20 KHz and digitizing the sampled signal at a volume precision of 70 Å3 a substantial majority of the proteins in a proteome can be identified and counted without labeling. Computations on the full set of sequences in the human proteome (Uniprot id UP000005640_9606) show that ~70% of the proteins can be identified; the result generally holds even when post-translational modifications (PTMs) are present. The identification rate can be increased to better than 95% with modified algorithms; with an array of 100 pores ~109 proteins can be identified/counted in about 1.5 hours. This is a minimalist non-destructive single molecule label-free approach that is based on unmodified nanopores; it serves as a potential alternative to mass spectrometry while overcoming many of the limitations of the latter. In principle it can work with whole proteins in mixtures over the full dynamic range of a proteome without purification/separation, proteolytic degradation, or enzymes for translocation control
Avoiding Reward Hacking in Multi-Objective Molecular Design: A Data-Driven Generative Strategy with a Reliable Design Framework
No full textMolecular design using data-driven generative models has emerged as a promising technology, impacting various fields such as drug discovery and the development of functional materials. However, this approach is often susceptible to optimization failure due to reward hacking, where prediction models fail to accurately predict properties for designed molecules that considerably deviate from the training data. While methods for estimating prediction reliability, such as the applicability domain (AD), have been proposed for mitigating reward hacking, multi-objective optimization makes it challenging. The difficulty arises from the need to determine in advance whether the multiple ADs with some reliability levels overlap in chemical space, and to appropriately adjust the reliability levels for each property prediction. Herein, we propose a reliable design framework to perform multi-objective optimization using generative models while preventing reward hacking. To demonstrate the effectiveness of the proposed framework, we designed candidates for anticancer drugs as a typical example of multi-objective optimization. We successfully designed molecules with high predicted values and reliabilities, including an approved drug. In addition, the reliability levels can be automatically adjusted according to the property prioritization specified by the user without any detailed settings. Our approach presents a solution to the essential problem of designing molecules using data-driven generative models
Dyeing to Know: Optimizing Solvents for Nile Red Fluorescence in Microplastics Analysis
No full textWith the escalation of microplastic (MP) pollution and the laborious nature of existing MP identification methods, new approaches for large-scale sampling of MPs in the environment are necessary. A promising solution lies in the fluorescence staining of Nile Red (NR), whose fluorescence is polarity-dependent, offering the potential for classification based on fluorescence. However, the choice of carrier solvents to dissolve NR remains unstandardized, and methods to represent and differentiate the fluorescent behavior of MPs are lacking. To address this gap, we conducted tests on eight NR-carrier solvents (n-hexane, chloroform, acetone, methanol, ethanol, acetone/hexane, acetone/ethanol, and acetone/water) applied to ten different types of MPs (HDPE, LDPE, PP, EPS, PS, PC, ABS, PVC, PET, and PA). We compared their fluorescence behavior (fluorescence intensity and Stokes shift), evaluated their effects on polymer degradation, and assessed the ability of different potential polarity measures and color spaces to accurately reflect Stokes shift for MP classification. Furthermore, Fenton oxidation was found to quench the fluorescence of natural organic matter (e.g., eggshells, fingernails, wood, and cotton), with minimal changes observed in NR-stained MPs. Our findings identified acetone/water [25%] as the best compromise, effectively mitigating the adverse effects of acetone while maintaining strong fluorescence behavior suitable for classification
Calculating Absorption and Fluorescence Spectra for Chromophores in Solution with Ensemble Franck-Condon Methods
No full textAccurately modeling absorption and fluorescence spectra for molecules in solution poses a challenge due to the need to incorporate both vibronic and environmental effects, as well as the necessity of accurate excited state electronic structure calculations. Nuclear ensemble approaches capture explicit environmental effects, Franck-Condon methods capture vibronic effects, and recently introduced ensemble-Franck-Condon approaches combine the advantages of both methods. In this study, we present and analyze simulated absorption and fluorescence spectra generated with combined ensemble-Franck-Condon approaches for three chromophore-solvent systems and compare them to standard ensemble and Franck-Condon spectra, as well as to experiment. Employing configurations obtained from ground and excited state ab initio molecular dynamics, three combined ensemble-Franck-Condon approaches are directly compared to each other to assess the accuracy and relative computational time. We find that the approach employing an average finite-temperature Franck-Condon lineshape generates spectra nearly identical to the direct summation of an ensemble of Franck-Condon spectra at one-fourth of the computational cost. We analyze how the spectral simulation method, as well as the level of electronic structure theory, affects spectral lineshapes and associated Stokes shifts for 7-nitrobenz-2-oxa-1,3-diazol-4-yl (NBD) and Nile Red in dimethyl sulfoxide (DMSO), and 7-methoxy coumarin-4-acetic acid (7MC) in methanol. For the first time, our studies showcase the capability of combined ensemble-Franck-Condon methods for both absorption and fluorescence spectroscopy and provide a powerful tool for simulating linear optical spectra
Combining Fourier Transform Ion Mobility with Charge Detection Mass Spectrometry for the Analysis of Multimeric Protein Complexes
No full textCharge detection mass spectrometry (CDMS) allows direct mass measurement of
heterogeneous samples by simultaneously determining the charge state and the mass-to-
charge ratio (m/z) of individual ions, unlike conventional MS methods that use large ensembles
of ions. CDMS typically requires long acquisition times and the collection of thousands of
spectra, each containing tens to hundreds of ions, to generate sufficient ion statistics, making it
difficult to interface with the time scales of online separation techniques such as ion mobility.
Here, we demonstrate the application of Fourier transform multiplexing and drift tube ion
mobility joined with Orbitrap-based CDMS for the analysis of multimeric protein complexes.
Stepped frequency modulation was utilized to enable unambiguous frequency assignment
during mobility sweeps and allow spectral averaging, which improves the accuracy and signal to
noise of arrival time distributions and CDMS measurements. Fourier transformation of the
signal reveals the arrival times and collision cross sections of ions while simultaneously
collecting charge information for thousands of individual ions. Combining Fourier transform
multiplexing ion mobility and CDMS provides insight into each ion’s size and mass while
showcasing a potential solution to the duty cycle mismatch of online separation techniques in
the single ion regime
BuildAMol: A versatile Python toolkit for fragment-based molecular design
No full textIn recent years computational methods for molecular modeling have become a prime focus of computational biology and cheminformatics. Many dedicated systems exist for modeling specific classes of molecules such as proteins or small drug-like ligands. These are often heavily tailored toward the automated gen- eration of molecular structures based on some meta-input by the user and are not intended for expert-driven structure assembly. Dedicated manual or semi- automated assembly software tools exist for a variety of molecule classes but are limited in the scope of structures they can produce. In this work we present BuildAMol, a highly flexible and extendable, general-purpose fragment-based molecular assembly toolkit. Written in Python and featuring a well-documented, user-friendly API, BuildAMol empowers researchers with a framework for detailed manual or semi-automated construction of diverse molecular models. Unlike specialized software, BuildAMol caters to a broad range of applications. We demonstrate its versatility across various use cases, encompassing generating metal complexes or the modeling of dendrimers or integrated into a drug discov- ery pipeline. By providing a robust foundation for expert-driven model building, BuildAMol holds promise as a valuable tool for the continuous integration and advancement of powerful deep learning techniques
Transforming Aryl-Tetrazines into Bioorthogonal Scissors for Systematic Cleavage of trans-Cyclooctenes
No full textBioorthogonal bond-cleavage reactions have emerged as a powerful tool for precise spatiotemporal control of (bio)molecular function in the biological context. Among these chemistries, the tetrazine-triggered elimination of cleavable trans-cyclooctenes (click-to-release) stands out due to high reaction rates, versatility, and selectivity. Despite an increasing understanding of the underlying mechanisms, application of this reaction remains limited by the cumulative performance trade-offs (i.e., click kinetics, release kinetics, release yield) of existing tools. Efficient release has been restricted to tetrazine scaffolds with comparatively low click reactivity, while highly reactive aryl-tetrazines give only minimal release. By introducing hydroxyl groups onto phenyl- and pyridyl-tetrazine scaffolds, we have developed a new class of ‘bioorthogonal scissors’ with unique chemical performance. We demonstrate that hydroxyaryl-tetrazines achieve near-quantitative release upon accelerated click reaction with cleavable trans-cyclooctenes, as exemplified by click-triggered activation of a caged prodrug, intramitochondrial cleavage of a fluorogenic probe (turn-on) in live cells, and rapid intracellular bioorthogonal disassembly (turn-off) of a ligand-dye conjugate
Computational Approach to Assessing the Effectiveness of Passive Control in Sheet, Cloud, and Supercavitation Regimes on the NACA4412 Cambered Hydrofoil
No full textCavitation is a transient, highly complex phenomenon found in numerous applications and can have a significant impact on the characteristics as well as the performance of the hydrofoils. This study compares the evolution of transient cavitating flow over a NACA4412 base hydrofoil and over the same hydrofoil modified with a pimple and a finite (circular) trailing edge. The assessment covers sheet, cloud, and supercavitation regimes at an 8° angle of attack and Reynolds number of 1×, with cavitation numbers ranging from 0.9 to 0.2. The study aims to comprehensively understand the role of the rectangular pimple in controlling cavitation and its impact on hydrodynamic performance across these regimes. Numerical simulations were performed using a realizable model and the Zwart Gerber-Belamri (ZGB) cavitation model to resolve turbulence and cavitation effects. The accuracy of the present numerical predictions has been verified both quantitatively and qualitatively with available experimental results. The present analysis includes the time evolution of cavities, temporal variation in total cavity volume, time-averaged total cavity volume, distributions of vapor volume fractions along the chord length, and their hydrodynamic performance parameters. Results demonstrate that rectangular pimples have significant impact in the different cavitation regimes. In the sheet cavitation regime (), the NACA4412(pimpled) hydrofoil exhibits minimal cavity length and transient volume changes as compared to the NACA4412(base) hydrofoil. In the cloud cavitation regimes (), cavity initiation occurs differently, starting from the pimpled location for the NACA4412(pimpled) hydrofoil, unlike the initiation just downstream of the nose in the case of base hydrofoil. In the supercavitation regimes (), the cavity length remains comparable, but the NACA4412(pimpled) pimpled hydrofoil exhibits larger cavity volume evolution in both cloud and supercavitation regimes ( \& ) after initial fluctuations. Furthermore, hydrodynamic performance for the NACA4412(pimpled) hydrofoil shows 41\%, 36\%, and 17\% lower lift coefficients, and 46\%, 27\%, and 9\% lower drag coefficients in sheet, cloud, and supercavitation, respectively