Computational Infrared Spectroscopy: Reproducing Kernel- and Multipolar-Based Force Field Simulations for Site-Selective Dynamics of Proteins

Characterizing the structural and functional dynamics of complex systems in the condensed phase requires fine spatial and/or temporal resolution which is a challenging problem, demanding vibrational probes that confer possible functional and steric variation on local properties. Vibrational time occurs in the femtosecond domain and frequencies are dependent on spatial arrangement and the characteristics of the constituent atoms. Therefore, vibrational spectroscopy has become an essential tool to study the structure and dynamics of various biological systems at the molecular level. However, achieving site-specific information on biological molecules of interest, such as proteins, is impossible in many cases or problematic to rely on the intrinsic vibrational modes. To overcome this limitation, the focus of this work is the development and application of several intrinsic backbone and side chain vibrational probes that can be easily incorporated into proteins and be used to site-specifically investigate their structural or environmental properties using reproducing kernel- and multipolar-based force field simulations

Site-Selective Dynamics of Ligand-Free and Ligand-Bound Azidolysozyme

Azido-modified alanine residues (AlaN3) are environment-sensitive, minimally invasive infrared probes for the site-specific investigation of protein structure and dynamics. Here, the capability of the label is investigated to query whether or not a ligand is bound to the active site of lysozyme and how the spectroscopy and dynamics change upon ligand binding. The results demonstrate specific differences for center frequencies of the asymmetric azide stretch vibration, the longtime decay, and the static offset of the frequency fluctuation correlation function (FFCF)—all of which are experimental observables—between the ligand-free and the ligand-bound N3-labeled protein. The center-frequency shifts range from 1 to 8 cm−1, which is detectable from state-of-the art experiments. Similarly, the nonvanishing static component Δ0 of the FFCF between ligand-free and ligand-bound protein can differ by up to a factor of 2.5. This makes the azide label a versatile and structurally sensitive probe to report on the dynamics of proteins in a variety of environments and for a range of different applications. Ligand-induced differences in the dynamics are also mapped onto changes in the local and through-space coupling between residues by virtue of dynamical cross correlation maps. This demonstrates that the position where the label is placed also influences the local and global protein motions

Effects of short-term accruals on the pricing of audit services

This study investigates the relationship between short-term accruals and pricing of audit services in the Tehran Stock Exchange during the period 2009-2014 will be discussed. For this study, the 90 companies listed in Tehran Stock Exchange for the period was determined. To test study hypothesis by regression analysis using software integrated in all companies use EViews6 In this study to determine the audit fees were used for short-term accruals. The dependent variable pricing study audit services to assess which of the four criteria, audit fees, the natural logarithm effort, the natural logarithm of the investment cost of the audit, the natural logarithm was used to increase the selling price. Also in this study, the control variables of the current debt ratio of short-term investments, financial debt ratio, return on assets, long-term financial leverage, the rate of depreciation expense, size, and variable operating loss was ambivalent. The findings suggest that short-term accruals and effort spent on the remuneration of the auditors' audit and the audit contract gross profit and significant positive impact, but the impact on the auditor's fee when the investment is negative and significant. In this study, the control variables depreciation expense spent on trying the resort's auditors have a positive impact and meaning. Keywords: short-term accruals, pricing of audit services, audit fees, effort, and money invested time auditor

Cross Correlated Motions in Azidolysozyme

The changes in the local and global dynamics of azide-labelled lysozyme compared with that of the wild type protein are quantitatively assessed for all alanine residues along the polypeptide chain. Although attaching -N3 to alanine residues has been considered to be a minimally invasive change in the protein it is found that depending on the location of the alanine residue, the local and global changes in the dynamics differ. For Ala92, the change in the cross-correlated motions are minimal, whereas attaching -N3 to Ala90 leads to pronounced differences in the local and global correlations as quantified by the cross-correlation coefficients of the Cα atoms. We also demonstrate that the spectral region of the asymmetric azide stretch distinguishes between alanine attachment sites, whereas changes in the low frequency, far-infrared region are less characteristic

Effects of Short-Term Accruals on the Pricing of Audit Services

This study investigates the relationship between short-term accruals and pricing of audit services in the Tehran Stock Exchange during the period 2009-2014 will be discussed. For this study, the 90 companies listed in Tehran Stock Exchange for the period was determined. To test study hypothesis by regression analysis using software integrated in all companies use EViews6 In this study to determine the audit fees were used for short-term accruals. The dependent variable pricing study audit services to assess which of the four criteria, audit fees, the natural logarithm effort, the natural logarithm of the investment cost of the audit, the natural logarithm was used to increase the selling price. Also in this study, the control variables of the current debt ratio of short-term investments, financial debt ratio, return on assets, long-term financial leverage, the rate of depreciation expense, size, and variable operating loss was ambivalent. The findings suggest that short-term accruals and effort spent on the remuneration of the auditors' audit and the audit contract gross profit and significant positive impact, but the impact on the auditor's fee when the investment is negative and significant. In this study, the control variables depreciation expense spent on trying the resort's auditors have a positive impact and meaning. Keywords: short-term accruals, pricing of audit services, audit fees, effort, and money invested time auditor

Site-Selective Dynamics of Azidolysozyme

The spectroscopic response of and structural dynamics around all azido-modified alanine residues (AlaN$_3$) in Lysozyme is characterized. It is found that AlaN$_3$ is a positionally sensitive probe for the local dynamics, covering a frequency range of $\sim 15$ cm$^{-1}$ for the center frequency of the line shape. This is consistent with findings from selective replacements of amino acids in PDZ2 which reported a frequency span of $\sim 10$ cm$^{-1}$ for replacements of Val, Ala, or Glu by azidohomoalanine (AHA). For the frequency fluctuation correlation functions (FFCFs) the long-time decay constants $\tau_2$ range from $\sim 1$ to $\sim 10$ ps which compares with experimentally measured correlation times of 3 ps. Attaching azide to alanine residues can yield dynamics that decays to zero on the few ps time scale (i.e. static component $\Delta_0 \sim 0$ ps$^{-1}$) or to a remaining, static contribution of $\sim 0.5$ ps$^{-1}$ (corresponding to 2.5 cm$^{-1}$), depending on the local environment on the 10 ps time scale. The magnitude of the static component correlates qualitatively with the degree of hydration of the spectroscopic probe. Although attaching azide to alanine residues is found to be structurally minimally invasive with respect to the overall protein structure, analysis of the local hydrophobicity indicates that the hydration around the modification site differs for modified and unmodified alanine residues, respectively.Comment: for MS: 33 page, 10 figures for SI: 6 pages, 9 figure

Trends in Medicinal Chemistry: KNIME Workflows, QSAR Models, LLMs and Chemical Search Strategies

Through a lens encompassing KNIME workflows, QSAR models, LLMs, and chemical substructure search strategies, the article navigates the essential considerations driving innovation and progress in industrial cheminformatics for medicinal chemistry and drug discovery

Hydration dynamics and IR spectroscopy of 4-fluorophenol

Halogenated groups are relevant in pharmaceutical applications and potentially useful spectroscopic probes for infrared spectroscopy. In this work, the structural dynamics and infrared spectroscopy of para-fluorophenol (F-PhOH) and phenol (PhOH) is investigated in the gas phase and in water using a combination of experiment and molecular dynamics (MD) simulations. The gas phase and solvent dynamics around F-PhOH and PhOH is characterized from atomistic simulations using empirical energy functions with point charges or multipoles for the electrostatics, Machine Learning (ML) based parametrizations and with full ab initio (QM) and mixed Quantum Mechanical/Molecular Mechanics (QM/MM) simulations with a particular focus on the CF- and OH-stretch region. The CF-stretch band is heavily mixed with other modes whereas the OH-stretch in solution displays a characteristic high-frequency peak around 3600 cm−1 most likely associated with the –OH group of PhOH and F-PhOH together with a characteristic progression below 3000 cm−1 due to coupling with water modes which is also reproduced by several of the simulations. Solvent and radial distribution functions indicate that the CF-site is largely hydrophobic except for simulations using point charges which renders them unsuited for correctly describing hydration and dynamics around fluorinated sites. The hydrophobic character of the CF-group is particularly relevant for applications in pharmaceutical chemistry with a focus on local hydration and interaction with the surrounding protein

Hydration dynamics and IR spectroscopy of 4-fluorophenol

Halogenated groups are relevant in pharmaceutical applications and potentially useful spectroscopic probes for infrared spectroscopy. In this work, the structural dynamics and infrared spectroscopy of para-fluorophenol (F-PhOH) and phenol (PhOH) is investigated in the gas phase and in water using a combination of experiment and molecular dynamics (MD) simulations. The gas phase and solvent dynamics around F-PhOH and PhOH is characterized from atomistic simulations using empirical energy functions with point charges or multipoles for the electrostatics, Machine Learning (ML) based parametrizations and with full ab initio (QM) and mixed Quantum Mechanical/Molecular Mechanics (QM/MM) simulations with a particular focus on the CF- and OH-stretch region. The CF-stretch band is heavily mixed with other modes whereas the OH-stretch in solution displays a characteristic high-frequency peak around 3600 cm−1 most likely associated with the –OH group of PhOH and F-PhOH together with a characteristic progression below 3000 cm−1 due to coupling with water modes which is also reproduced by several of the simulations. Solvent and radial distribution functions indicate that the CF-site is largely hydrophobic except for simulations using point charges which renders them unsuited for correctly describing hydration and dynamics around fluorinated sites. The hydrophobic character of the CF-group is particularly relevant for applications in pharmaceutical chemistry with a focus on local hydration and interaction with the surrounding protein