| 1. |
- Aaldering, L. J., et al.
(författare)
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Development of an Efficient G-Quadruplex-Stabilised Thrombin-Binding Aptamer Containing a Three-Carbon Spacer Molecule
- 2017
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Ingår i: ChemBioChem (Print). - : Wiley-VCH Verlag. - 1439-4227 .- 1439-7633. ; 18:8, s. 755-763
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Tidskriftsartikel (refereegranskat)abstract
- The thrombin-binding aptamer (TBA), which shows anticoagulant properties, is one of the most studied G-quadruplex-forming aptamers. In this study, we investigated the impact of different chemical modifications such as a three-carbon spacer (spacer-C3), unlocked nucleic acid (UNA) and 3′-amino-modified UNA (amino-UNA) on the structural dynamics and stability of TBA. All three modifications were incorporated at three different loop positions (T3, T7, T12) of the TBA G-quadruplex structure to result in a series of TBA variants and their stability was studied by thermal denaturation; folding was studied by circular dichroism spectroscopy and thrombin clotting time. The results showed that spacer-C3 introduction at the T7 loop position (TBA-SP7) significantly improved stability and thrombin clotting time while maintaining a similar binding affinity as TBA to thrombin. Detailed molecular modelling experiments provided novel insights into the experimental observations, further supporting the efficacy of TBA-SP7. The results of this study could provide valuable information for future designs of TBA analogues with superior thrombin inhibition properties.
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| 2. |
- Andersson, Måns, et al.
(författare)
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Breaking Down the Parallel Performance of GROMACS, a High-Performance Molecular Dynamics Software
- 2023
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Ingår i: PPAM 2022. Lecture Notes in Computer Science, vol 13826.. - : Springer Nature. ; , s. 333-345
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Konferensbidrag (refereegranskat)abstract
- GROMACS is one of the most widely used HPC software packages using the Molecular Dynamics (MD) simulation technique. In this work, we quantify GROMACS parallel performance using different configurations, HPC systems, and FFT libraries (FFTW, Intel MKL FFT, and FFT PACK). We break down the cost of each GROMACS computational phase and identify non-scalable stages, such as MPI communication during the 3D FFT computation when using a large number of processes. We show that the Particle-Mesh Ewald phase and the 3D FFT calculation significantly impact the GROMACS performance. Finally, we discuss performance opportunities with a particular interest in developing GROMACS for the FFT calculations.
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| 3. |
- Ashaduzzaman, Md., et al.
(författare)
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On/off-switchable LSPR nano-immunoassay for troponin-T
- 2017
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Ingår i: Scientific Reports. - : Springer Nature. - 2045-2322. ; 7:1
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Tidskriftsartikel (refereegranskat)abstract
- Regeneration of immunosensors is a longstanding challenge. We have developed a re-usable troponin-T (TnT) immunoassay based on localised surface plasmon resonance (LSPR) at gold nanorods (GNR). Thermosensitive poly(N-isopropylacrylamide) (PNIPAAM) was functionalised with anti-TnT to control the affinity interaction with TnT. The LSPR was extremely sensitive to the dielectric constant of the surrounding medium as modulated by antigen binding after 20 min incubation at 37 degrees C. Computational modelling incorporating molecular docking, molecular dynamics and free energy calculations was used to elucidate the interactions between the various subsystems namely, IgG-antibody (c. f., anti-TnT), PNIPAAM and/or TnT. This study demonstrates a remarkable temperature dependent immuno-interaction due to changes in the PNIPAAM secondary structures, i.e., globular and coil, at above or below the lower critical solution temperature (LCST). A series of concentrations of TnT were measured by correlating the lambda(LSPR) shift with relative changes in extinction intensity at the distinct plasmonic maximum (i. e., 832 nm). The magnitude of the red shift in lambda(LSPR) was nearly linear with increasing concentration of TnT, over the range 7.6 x 10(-15) to 9.1 x 10(-4) g/mL. The LSPR based nano-immunoassay could be simply regenerated by switching the polymer conformation and creating a gradient of microenvironments between the two states with a modest change in temperature.
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| 4. |
- Ashaduzzaman, M., et al.
(författare)
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Studies on an on/off-switchable immunosensor for troponin T
- 2015
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Ingår i: Biosensors & bioelectronics. - : Elsevier BV. - 0956-5663 .- 1873-4235. ; 73
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Tidskriftsartikel (refereegranskat)abstract
- Regeneration is a key goal in the design of immunosensors. In this study, we report the temperature-regulated interaction of N-isopropylacrylamide (PNIPAAm) functionalised cardiac troponin T (cTnT) with anti-cTnT. Covalently bonded PNIPAAm on an anti-cTnT bioelectrode showed on/off-switchability, regeneration capacity and temperature triggered sensitivity for cTnT. Above the lower critical solution temperature (LCST), PNIPAAm provides a liphophilic microenvironment with specific volume reduction at the bioelectrode surface, making available binding space for cTnT, and facilitating analyte recognition. Computational studies provide details about the structural changes occurring at the electrode above and below the LCST. Furthermore, free energies associated with the binding of cTnT with PNIPAAm at 25 (δGcoil=-6.0Kcal/mole) and 37°C (δGglobular=-41.0kcal/mole) were calculated to elucidate the interaction and stability of the antigen-antibody complex. The responsiveness of such assemblies opens the way for miniaturised, smart immuno-technologies with 'built-in' programmable interactions of antigen-antibody upon receiving stimuli.
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| 5. |
- Balamurugan, Kanagasabai, et al.
(författare)
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Effect of Alzheimer Familial Chromosomal Mutations on the Amyloid Fibril Interaction with Different PET Tracers : Insight from Molecular Modeling Studies
- 2017
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Ingår i: ACS Chemical Neuroscience. - : American Chemical Society (ACS). - 1948-7193. ; 8:12, s. 2655-2666
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Tidskriftsartikel (refereegranskat)abstract
- Alzheimer's disease (AD) is the most common neurodegenerative disorder. Along with an increasing number of elderly worldwide, it poses a great challenge for the society and health care. Although sporadic AD is the common form of AD, 2-3% of the AD cases are expected to be due to mutations in the fi region of the amyloid precursor protein, which is referred to as autosomal dominant AD (ADAD). These mutations may cause changes in the secondary structure of the amyloid fi fibrils and may alter the fibrillization rate leading to changes in the disease development and could also affect the binding to tracers used in diagnosis. In particular, from some recent clinical studies using PET tracers for detection of fibrillar amyloids, it is evident that in ADAD patients with Arctic mutation no amyloid plaque binding can be detected with the "C Pittsburgh Compound B (C-11-PIB). However, for in vitro conditions, significant binding of H-3-PIB has been reported for the amyloid fibrils carrying the Arctic mutation. The aim of the present study is to investigate if there is any mutation specific binding of commonly used amyloid tracers, namely, florbetaben, florbetapir, FPIB, AZD4694, and AZD2184, by means of molecular modeling techniques. Other than Arctic, ADAD mutations, such as the Dutch, Italian, Iowa, and Flemish mutations, are considered in this study. We report that all tracers except florbetapir show reduced binding affinity toward amyloid beta fibrils with the Arctic mutation when compared to the native type. Moreover, florbetapir is the only tracer that binds to all mutants with increased affinity when compared to the native fibril. The results obtained from these studies could increase the understanding of the structural changes caused by mutation and concomitant changes in the interaction pattern of the PET tracers with the mutated variants, which in turn can be useful in selecting the appropriate tracers for the purpose of diagnosis as well as for designing new tracers with desirable properties.
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| 6. |
- Balamurugan, Kanagasabai, et al.
(författare)
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Multistep Modeling Strategy To Improve the Binding Affinity Prediction of PET Tracers to A beta(42) : Case Study with Styrylbenzoxazole Derivatives
- 2016
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Ingår i: ACS CHEMICAL NEUROSCIENCE. - : American Chemical Society (ACS). - 1948-7193. ; 7:12, s. 1698-1705
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Tidskriftsartikel (refereegranskat)abstract
- Positron emission tomography (PET) tracers play an important role in the diagnosis of Alzheimer's disease, a condition that leads to progressive dementia and memory loss. A high binding affinity and specificity of the PET tracers to amyloid oligomers and fibrils are crucial for their successful application as diagnostic agents. In this sense, it is essential to design PET tracers with enhanced binding affinities, which can lead to more precise and earlier detection of Alzheimer's disease conditions. The application of in silico methodology for the design and development of efficient PET tracers may serve as an important route to improved Alzheimer's disease diagnosis. In this work, the performance of widely used computational methods is explored for predicting experimental binding affinities of styrylbenzoxazole (SB) derivatives against a common amyloid protofibril. By performing docking, molecular dynamics, and quantum chemistry calculations in sequence their combined predictive performance is explored. The present work emphasizes the merits as well as limitations of these simulation strategies in the realm of designing PET tracers for Alzheimer's disease diagnosis.
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| 7. |
- Bednarska, Joanna, et al.
(författare)
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Nonempirical Simulations of Inhomogeneous Broadening of Electronic Transitions in Solution : Predicting Band Shapes in One- and Two-Photon Absorption Spectra of Chalcones
- 2017
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Ingår i: Molecules. - : MDPI AG. - 1431-5157 .- 1420-3049. ; 22:10
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Tidskriftsartikel (refereegranskat)abstract
- We have examined several approaches relying on the Polarizable Embedding (PE) scheme to predict optical band shapes for two chalcone molecules in methanol solution. The PE-TDDFT and PERI-CC2 methods were combined with molecular dynamics simulations, where the solute geometry was kept either as rigid, flexible or partly-flexible (restrained) body. The first approach, termed RBMD-PE-TDDFT, was employed to estimate the inhomogeneous broadening for subsequent convolution with the vibrationally-resolved spectra of the molecule in solution determined quantum-mechanically (QM). As demonstrated, the RBMD-PE-TDDFT/QM-PCM approach delivers accurate band widths, also reproducing their correct asymmetric shapes. Further refinement can be obtained by the estimation of the inhomogeneous broadening using the RBMD-PERI-CC2 method. On the other hand, the remaining two approaches (FBMD-PE-TDDFT and ResBMD-PE-TDDFT), which lack quantum-mechanical treatment of molecular vibrations, lead to underestimated band widths. In this study, we also proposed a simple strategy regarding the rapid selection of the exchange-correlation functional for the simulations of vibrationally-resolved one-and two-photon absorption spectra based on two easy-to-compute metrics.
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| 8. |
- Biswas, B., et al.
(författare)
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Near-infrared emissive cyanine probes for selective visualization of the physiological and pathophysiological modulation of albumin levels
- 2022
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Ingår i: Journal of materials chemistry. B. - : Royal Society of Chemistry (RSC). - 2050-750X .- 2050-7518.
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Tidskriftsartikel (refereegranskat)abstract
- With the promising advantages of the near-infrared region (NIR) emissive markers for serum albumin becoming very prominent recently, we devised CyG-NHS as the cyanine derived longest NIR-I emissive optical marker possessing albumin selective recognition ability in diverse biological milieu. Multiscale modeling involving molecular docking, molecular dynamics, and implicit solvent binding free energy calculations have been employed to gain insights into the unique binding ability of the developed probe at domain-I of albumin, in contrast to the good number of domain IIA or IIIA binding probes available in the literature reports. The binding free energy was found to be −31.8 kcal mol−1 majorly predominated by hydrophobic interactions. Besides, the conformational dynamics of CyG-NHS in an aqueous medium and the albumin microenvironment have been comprehensively studied and discussed. The potentiality of this optical platform to monitor the intracellular albumin levels in human hepatoma (HepG2) cells in different pathophysiological states has been demonstrated here. Also, the competency of the phenformin drug in restoring the albumin levels in chronic hyperinsulinemic and hypercholesterolemic in vitro models has been established through the visualization approach. Altogether, the findings of this study throw light on the significance of the development of a suitable optical marker for the visualization of critical bioevents related to albumin.
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| 9. |
- de Almeida, Katia Júlia, et al.
(författare)
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Conformations, structural transitions and visible near-infrared absorption spectra of four-, five- and six-coordinated Cu(II) aqua complexes
- 2009
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Ingår i: Physical Chemistry, Chemical Physics - PCCP. - : Royal Society of Chemistry (RSC). - 1463-9076 .- 1463-9084. ; 11:3, s. 508-519
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Tidskriftsartikel (refereegranskat)abstract
- We have performed Car-Parrinello molecular dynamics simulations at ambient conditions for four-, five- and six-coordinated Cu(II) aqua complexes. The molecular geometry has been investigated in terms of Cu-O, Cu-H bond lengths and O-Cu-O bond angles and compared with earlier experimental measurement results and theoretical calculations. We find that the average Cu-O and Cu-H bond lengths increase with increasing coordination number. We have also observed relatively faster structural transition in the case of five- coordinated complex between trigonal bipyramidal and square pyramidal geometry. This result deviates from the findings of the earlier report (A. Pasquarello et al., Science, 2001, 291, 856) on copper( II) in aqueous solution and we attribute these differences to the neglect of solvent environment in our calculations. The averaged absorption spectra for the copper( II) aqua complexes have been computed using spin-restricted density functional linear response formalism taking 100 snap shots from a trajectory of 0.48 ps. We find that the calculated spectra are significantly different, showing clear features that distinguish each coordination model. Comparison with the experimentally reported absorption spectra is made wherever it is possible and the results obtained favor the distorted fivefold-coordination arrangement for the molecular structure of the Cu(II) ion in aqueous solution.
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| 10. |
- Frecus, Bogdan, et al.
(författare)
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EPR spin Hamiltonian parameters of encapsulated spin-labels : impact of the hydrogen bonding topology
- 2013
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Ingår i: Physical Chemistry, Chemical Physics - PCCP. - : Royal Society of Chemistry (RSC). - 1463-9076 .- 1463-9084. ; 15:7, s. 2427-2434
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Tidskriftsartikel (refereegranskat)abstract
- Encapsulation of spin-labels into "host'' compounds, like cucurbit[n]urils or cyclodextrins, in solutions has profound effects on the EPR spin Hamiltonian parameters of the spin-labels. In this work we study the microscopic origin of the EPR spin Hamiltonian parameters of spin-labels enclosed in hydrophobic cavities. We focus on the dependence of the EPR properties of encapsulated spin-labels on the hydrogen bonding topologies that occur upon encapsulation, and quantize various contributions to these parameters according to specific hydrogen bonding patterns. The obtained results provide refined insight into the role of the hydrogen bonding induced encapsulation shifts of EPR spin Hamiltonian parameters in solvated "spin-label@host compound'' complexes.
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