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

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

<p>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.</p>

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

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

<p>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.</p>

scholarly journals Identifying conformational isomers of organic molecules in solution via unsupervised clustering

2021 ◽  
Author(s):  
Veselina Marinova ◽  
Laurence Dodd ◽  
Song-Jun Lee ◽  
Geoffrey P. F. Wood ◽  
Ivan Marziano ◽  
...  
Keyword(s):  
Degrees Of Freedom ◽  
Systematic Approach ◽  
Organic Molecules ◽  
Unsupervised Clustering ◽  
Conformational Space ◽  
Energetic Cost ◽  
Conformational Ensemble ◽  
Conformational Isomers ◽  
Density Peaks ◽  
Crystal Bulk

<p>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.</p>

scholarly journals Identifying conformational isomers of organic molecules in solution via unsupervised clustering

2021 ◽  
Author(s):  
Veselina Marinova ◽  
Laurence Dodd ◽  
Song-Jun Lee ◽  
Geoffrey P. F. Wood ◽  
Ivan Marziano ◽  
...  
Keyword(s):  
Degrees Of Freedom ◽  
Systematic Approach ◽  
Organic Molecules ◽  
Unsupervised Clustering ◽  
Conformational Space ◽  
Energetic Cost ◽  
Conformational Ensemble ◽  
Conformational Isomers ◽  
Density Peaks ◽  
Crystal Bulk

<p>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.</p>

scholarly journals Solution and gas-phase modifiers effect on heme proteins environment and conformational space

2018 ◽  
Author(s):  
D. Butcher ◽  
J. Miksovska ◽  
M. E. Ridgeway ◽  
M. A. Park ◽  
F. Fernandez-Lima
Keyword(s):  
Gas Phase ◽  
Ion Mobility ◽  
Heme Proteins ◽  
Organic Molecules ◽  
Tertiary Structure ◽  
Organic Content ◽  
Conformational Space ◽  
Starting Solution ◽  
Trapped Ion Mobility Spectrometry ◽  
Secondary And Tertiary Structure

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.

scholarly journals Collisional excitation of complex organic molecules

2008 ◽  
Vol 4 (S251) ◽  
pp. 137-138 ◽  
Author(s):  
Alexandre Faure ◽  
Eric Josselin ◽  
Laurent Wiesenfeld ◽  
Cecilia Ceccarelli
Keyword(s):  
Gas Phase ◽  
Degrees Of Freedom ◽  
Organic Molecules ◽  
Low Frequency ◽  
Rate Coefficients ◽  
Collisional Excitation ◽  
Phase Complex ◽  
Collisional Rate Coefficients ◽  
Complex Organic ◽  
Collisional Rate

AbstractA major difficulty in modelling the infrared and (sub)millimeter spectra of gas-phase complex organic molecules is the lack of state-to-state collisional rate coefficients. Accurate quantum or classical scattering calculations for large polyatomic species are indeed computationally highly challenging, particularly when both rotation and low frequency vibrations such as bending and torsional modes are involved. We briefly present here an approximate approach to estimate and/or extrapolate rotational and rovibrational rates for polyatomic molecules with many degrees of freedom.

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

2019 ◽  
Vol 33 (5) ◽  
pp. 399-404 ◽  
Author(s):  
David Butcher ◽  
Jaroslava Miksovska ◽  
Mark E. Ridgeway ◽  
Melvin A. Park ◽  
Francisco Fernandez‐Lima
Keyword(s):  
Gas Phase ◽  
Heme Proteins ◽  
Conformational Space

scholarly journals Dynamical Behavior and Conformational Selection Mechanism of the Intrinsically Disordered Sic1 Kinase-Inhibitor Domain

Life ◽  
2020 ◽  
Vol 10 (7) ◽  
pp. 110 ◽  
Author(s):  
Davide Sala ◽  
Ugo Cosentino ◽  
Anna Ranaudo ◽  
Claudio Greco ◽  
Giorgio Moro
Keyword(s):  
Kinase Inhibitor ◽  
Dynamical Behavior ◽  
Md Simulations ◽  
Molecular Shape ◽  
Conformational Space ◽  
Coarse Grained ◽  
Conformational Ensemble ◽  
Selection Mechanism ◽  
Conformational Selection ◽  
Intrinsically Disordered

Intrinsically Disordered Peptides and Proteins (IDPs) in solution can span a broad range of conformations that often are hard to characterize by both experimental and computational methods. However, obtaining a significant representation of the conformational space is important to understand mechanisms underlying protein functions such as partner recognition. In this work, we investigated the behavior of the Sic1 Kinase-Inhibitor Domain (KID) in solution by Molecular Dynamics (MD) simulations. Our results point out that application of common descriptors of molecular shape such as Solvent Accessible Surface (SAS) area can lead to misleading outcomes. Instead, more appropriate molecular descriptors can be used to define 3D structures. In particular, we exploited Weighted Holistic Invariant Molecular (WHIM) descriptors to get a coarse-grained but accurate definition of the variegated Sic1 KID conformational ensemble. We found that Sic1 is able to form a variable amount of folded structures even in absence of partners. Among them, there were some conformations very close to the structure that Sic1 is supposed to assume in the binding with its physiological complexes. Therefore, our results support the hypothesis that this protein relies on the conformational selection mechanism to recognize the correct molecular partners.

scholarly journals The structural heterogeneity of α-synuclein is governed by several distinct subpopulations with interconversion times slower than milliseconds

2020 ◽  
Author(s):  
Jiaxing Chen ◽  
Sofia Zaer ◽  
Paz Drori ◽  
Joanna Zamel ◽  
Khalil Joron ◽  
...  
Keyword(s):  
Single Molecule ◽  
Resonance Energy Transfer ◽  
Resonance Energy ◽  
Intrinsically Disordered Protein ◽  
Structural Heterogeneity ◽  
Conformational Space ◽  
Conformational Ensemble ◽  
Time Resolved ◽  
Intrinsically Disordered ◽  
Transient Nature

AbstractThe intrinsically disordered protein, α-synuclein, implicated in synaptic vesicle homeostasis and neurotransmitter release, is also associated with several neurodegenerative diseases. The different roles of α-synuclein are characterized by distinct structural states (membrane-bound, dimer, tetramer, oligomer, and fibril), which are originated from its various monomeric conformations. The pathological states, determined by the ensemble of α-synuclein monomer conformations and dynamic pathways of interconversion between dominant states, remain elusive due to their transient nature. Here, we use inter-dye distance distributions from bulk time-resolved Förster resonance energy transfer as restraints in discrete molecular dynamics simulations to map the conformational space of the α-synuclein monomer. We further confirm the generated conformational ensemble in orthogonal experiments utilizing far-UV circular dichroism and cross-linking mass spectrometry. Single-molecule protein-induced fluorescence enhancement measurements show that within this conformational ensemble, some of the conformations of α-synuclein are surprisingly stable, exhibiting conformational transitions slower than milliseconds. Our comprehensive analysis of the conformational ensemble reveals essential structural properties and potential conformations that promote its various functions in membrane interaction or oligomer and fibril formation.

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