The effects of solution additives and gas‐phase modifiers on the molecular environment and conformational space of common heme proteins

AbstractThe molecular environment is known to impact the secondary and tertiary structure of biomolecules, shifting the equilibrium between different conformational and oligomerization states. In the present study, the effect of solution additives and gas-phase modifiers on the molecular environment of two common heme proteins, bovine cytochrome c and equine myoglobin, is investigated as a function of the time after desolvation (e.g., 100 - 500 ms) using trapped ion mobility spectrometry – mass spectrometry. Changes in the mobility profiles are observed depending on the starting solution composition (i.e., in aqueous solution at neutral pH or in the presence of organic content: methanol, acetone, or acetonitrile) depending on the protein. In the presence of gas-phase modifiers (i.e., N2 containing methanol, acetone, or acetonitrile), a shift in the mobility profiles driven by the gas-modifier mass and size and changes in the relative abundances and number of IMS bands are observed. We attribute these changes in the mobility profiles in the presence of gas-phase modifiers to a clustering/declustering mechanism by which organic molecules adsorb to the protein ion surface and lower energetic barriers for interconversion between conformational states, thus redefining the free energy landscape and equilibria between conformers. These structural biology experiments open new avenues for manipulation and interrogation of biomolecules in the gas-phase with the potential to emulate a large suite of solution conditions, ultimately including conditions that more accurately reflect a variety of intracellular environments.

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Structural analysis and probing the conformational space of dansylamide by means of gas-phase electron diffraction and quantum chemistry

Structural Chemistry ◽

10.1007/s11224-018-1108-2 ◽

2018 ◽

Vol 29 (3) ◽

pp. 823-835 ◽

Cited By ~ 1

Author(s):

Marwan Dakkouri ◽

Georgiy Girichev ◽

Nina Giricheva ◽

Vjacheslav Petrov ◽

Valentina Petrova

Keyword(s):

Structural Analysis ◽

Electron Diffraction ◽

Quantum Chemistry ◽

Gas Phase ◽

Conformational Space ◽

Gas Phase Electron Diffraction

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Elucidating the multiple structures of pipecolic acid by rotational spectroscopy

Physical Chemistry Chemical Physics ◽

10.1039/c8cp06120c ◽

2019 ◽

Vol 21 (8) ◽

pp. 4155-4161 ◽

Cited By ~ 4

Author(s):

A. Simão ◽

C. Cabezas ◽

I. León ◽

E. R. Alonso ◽

S. Mata ◽

...

Keyword(s):

Amino Acid ◽

Gas Phase ◽

Theoretical Data ◽

Pipecolic Acid ◽

Conformational Space ◽

Rotational Spectroscopy ◽

Multiple Structures ◽

First Time

The complex conformational space of the non-proteinogenic cyclic amino acid pipecolic acid has been explored in the gas phase for the first time, with 9 conformers characterized via a combination of CP-FTMW and LA-FTMW techniques, supported by theoretical data.

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Conformational Space of thePseudosaccharin Allyl Ether 3-(Allyloxy)-1,2-benzisothiazole 1,1-Dioxide in Gas Phase and in Rare Gas Matrices

The Journal of Physical Chemistry A ◽

10.1021/jp0770918 ◽

2008 ◽

Vol 112 (8) ◽

pp. 1762-1772 ◽

Cited By ~ 6

Author(s):

Andrea Gómez-Zavaglia ◽

Agnieszka Kaczor ◽

Rui Almeida ◽

Maria de Lurdes S. Cristiano ◽

Rui Fausto

Keyword(s):

Gas Phase ◽

Conformational Space ◽

Allyl Ether ◽

Rare Gas

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Polyalanine gas phase acidities determination and conformational space analysis by genetic algorithm assessment

10.31221/osf.io/xt9cm ◽

2019 ◽

Author(s):

Chem Int

Keyword(s):

Genetic Algorithm ◽

Gas Phase ◽

Energy Surface ◽

Conformational Space ◽

Am1 Method ◽

The One ◽

Semi Empirical ◽

Global And Local ◽

Formation Energies ◽

Good Agreement

The genetic algorithm, based on the Multi-Niche Crowding (MNC) method, coupled with the semi-empirical AM1 method is used to analyze the potential energy surface of some polypeptides containing cysteine. Calculating the formation energies of these systems in both neutral and deprotonated states, we deducted their enthalpy of deprotonation (ΔHacid) and we identified the types of rearrangement of these systems when isolated. Deprotonation occurs at the level of the alone acid site characterizing these peptides namely the thiol. The values obtained for the deprotonation enthalpies of polypeptides AlaCysNH2, Ala2CysNH2, Ala3CysNH2, Ala4CysNH2, CysAlaNH2 and CysAla2NH2 are in the order of 331.3 kcal/mol, 322.9 kcal/mol, 313.8 kcal/mol, 312.9 kcal/mol, 325.1 kcal/mol and 317.3 kcal/mol, respectively. The location of global and local minima of these polypeptides shows that they are rearranged in two forms of secondary structures namely helical and globular forms. The obtained results are in good agreement with the experimental ones, on the one hand, and with those from other methods in the theoretical calculation, on the other hand. Therefore, the N-cysteine is more acidic than their homologous C-Cysteine and for this series of plolyalanines, the acidity in the gas phase increased with the peptide chain length.

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Is a Single Conformer Sufficient to Describe the Reorganization Energy of Amorphous Organic Transport Materials?

10.26434/chemrxiv.13604057 ◽

2021 ◽

Author(s):

Jacob Terence Blaskovits ◽

Kun-Han Lin ◽

Raimon Fabregat ◽

Iwona Swiderska ◽

Hélène Wu ◽

...

Keyword(s):

Gas Phase ◽

Reorganization Energy ◽

Structural Rearrangement ◽

Hole Transport ◽

Conformational Space ◽

Molecular Solids ◽

Cautionary Tale ◽

A Charge ◽

Single Conformer ◽

Key Parameter

The reorganization energy (λ), which quantifies the structural rearrangement of a molecule when accommodating a charge, is a key parameter in the evaluation of charge mobility in molecular solids. However, it is unclear how λ is influenced by conformational isomerism, which co-exist in amorphous solids. Here, we examine the conformational space of a family of model amorphous organic hole transport materials (HTMs), derived from triphenylamine in a core-arm template, and probe the effect of conformational complexity on λ. We observe an extreme dependence of λ on the conformer geometry of sterically congested HTMs, which to the best of our knowledge has not been described previously. These results serve as a cautionary tale that, while extracting the reorganization energy from a single molecular conformer optimized in the gas phase may be appropriate for rigid and sterically unencumbered structures, it is not for many state-of-the-art HTMs that contain multiple bulky substituents.

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Spectroscopic studies of kinetically trapped conformations in the gas phase: the case of triply protonated bradykinin

Physical Chemistry Chemical Physics ◽

10.1039/c5cp01651g ◽

2015 ◽

Vol 17 (39) ◽

pp. 25828-25836 ◽

Cited By ~ 28

Author(s):

Liudmila Voronina ◽

Thomas R. Rizzo

Keyword(s):

Gas Phase ◽

Spectroscopic Studies ◽

Conformational Space

We explore conformational space of triply protonated bradykinin. Three conformational families are mobility-separated and spectroscopically characterized. Kinetically trapped structures are identified via annealing.

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Modeling the Thermodynamics of Conformational Isomerism in Solution via Unsupervised Clustering: The Case of Sildenafil

10.26434/chemrxiv.13247309 ◽

2020 ◽

Author(s):

Veselina Marinova ◽

Laurence Dodd ◽

Song-Jun Lee ◽

Geoffrey P. F. Wood ◽

Ivan Marziano ◽

...

Keyword(s):

Gas Phase ◽

Degrees Of Freedom ◽

Systematic Approach ◽

Organic Molecules ◽

Unsupervised Clustering ◽

Conformational Space ◽

Energetic Cost ◽

Conformational Ensemble ◽

Density Peaks ◽

Crystal Bulk

We present a systematic approach for the identification of statistically relevant conformational macrostates of organic molecules from molecular dynamics trajectories. The approach applies to molecules characterised by an arbitrary number of torsional degrees of freedom and enables the transferability of the macrostates definition across different environments. We formulate a dissimilarity measure between molecular configurations that incorporates information on the characteristic energetic cost associated with transitions along all relevant torsional degrees of freedom. Such metric is employed to perform unsupervised clustering of molecular configurations based on the fast search and find of density peaks algorithm. We apply this method to investigate the equilibrium conformational ensemble of Sildenafil, a conformationally complex pharmaceutical compound, in different environments including the crystal bulk, the gas phase and three different solvents (acetonitrile, 1-butanol, and toluene). We demonstrate that, while Sildenafil can adopt more than one hundred metastable conformational configurations, only 12 are significantly populated across all the environments investigated. Despite the complexity of the conformational space, we find that the most abundant conformers in solution are the closest to the conformers found in the most common Sildenafil crystal phase.

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Modeling the Thermodynamics of Conformational Isomerism in Solution via Unsupervised Clustering: The Case of Sildenafil

10.26434/chemrxiv.13247309.v1 ◽

2020 ◽

Author(s):

Veselina Marinova ◽

Laurence Dodd ◽

Song-Jun Lee ◽

Geoffrey P. F. Wood ◽

Ivan Marziano ◽

...

Keyword(s):

Gas Phase ◽

Degrees Of Freedom ◽

Systematic Approach ◽

Organic Molecules ◽

Unsupervised Clustering ◽

Conformational Space ◽

Energetic Cost ◽

Conformational Ensemble ◽

Density Peaks ◽

Crystal Bulk

We present a systematic approach for the identification of statistically relevant conformational macrostates of organic molecules from molecular dynamics trajectories. The approach applies to molecules characterised by an arbitrary number of torsional degrees of freedom and enables the transferability of the macrostates definition across different environments. We formulate a dissimilarity measure between molecular configurations that incorporates information on the characteristic energetic cost associated with transitions along all relevant torsional degrees of freedom. Such metric is employed to perform unsupervised clustering of molecular configurations based on the fast search and find of density peaks algorithm. We apply this method to investigate the equilibrium conformational ensemble of Sildenafil, a conformationally complex pharmaceutical compound, in different environments including the crystal bulk, the gas phase and three different solvents (acetonitrile, 1-butanol, and toluene). We demonstrate that, while Sildenafil can adopt more than one hundred metastable conformational configurations, only 12 are significantly populated across all the environments investigated. Despite the complexity of the conformational space, we find that the most abundant conformers in solution are the closest to the conformers found in the most common Sildenafil crystal phase.

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Is a Single Conformer Sufficient to Describe the Reorganization Energy of Amorphous Organic Transport Materials?

10.26434/chemrxiv.13604057.v1 ◽

2021 ◽

Author(s):

Jacob Terence Blaskovits ◽

Kun-Han Lin ◽

Raimon Fabregat ◽

Iwona Swiderska ◽

Hélène Wu ◽

...

Keyword(s):

Gas Phase ◽

Reorganization Energy ◽

Structural Rearrangement ◽

Hole Transport ◽

Conformational Space ◽

Molecular Solids ◽

Cautionary Tale ◽

A Charge ◽

Single Conformer ◽

Key Parameter

The reorganization energy (λ), which quantifies the structural rearrangement of a molecule when accommodating a charge, is a key parameter in the evaluation of charge mobility in molecular solids. However, it is unclear how λ is influenced by conformational isomerism, which co-exist in amorphous solids. Here, we examine the conformational space of a family of model amorphous organic hole transport materials (HTMs), derived from triphenylamine in a core-arm template, and probe the effect of conformational complexity on λ. We observe an extreme dependence of λ on the conformer geometry of sterically congested HTMs, which to the best of our knowledge has not been described previously. These results serve as a cautionary tale that, while extracting the reorganization energy from a single molecular conformer optimized in the gas phase may be appropriate for rigid and sterically unencumbered structures, it is not for many state-of-the-art HTMs that contain multiple bulky substituents.

Download Full-text