Surface excess free energies and equilibrium Wulff shapes in variable chemical environments at finite temperatures

<div>Charged droplets play a central role in native mass spectrometry, atmospheric aerosols and in serving as micro-reactors for accelerating chemical reactions. The surface excess charge layer in droplets has often been associated with distinct chemistry. Using molecular simulations for droplets with Na+ and Cl- ions we have found that this layer is ≈ 1.5−1.7 nm thick and depending on the droplet size it includes 33%-55% of the total number of ions. Here, we examine the eﬀect of droplet size and nature of ions in the structure of the surface excess charge layer by using molecular dynamics. We ﬁnd that in the presence of simple ions the thickness of the surface excess charge layer is invariant not only with respect to droplet size but also with respect to the nature of the simple ions and it is not sensitive to ﬁne details of diﬀerent force ﬁelds used in our simulations.</div><div> In the presence of macroions the excess surface charge layer may extend to 2.0. nm. For the same droplet size, iodide and model hydronium ions show considerably higher concentration than the sodium and chloride ions. <br></div><div>We also ﬁnd that diﬀerences in the average water dipole orientation in the presence of cations and anions in this layer are reﬂected in the charge distributions. Within the surface charge layer, the number of hydrogen bonds reduces gradually relative to the droplet interior where the number of hydrogen bonds is on the average 2.9 for droplets of diameter < 4 nm and 3.5 for larger droplets. The decrease in the number of hydrogen bonds from the interior to the surface is less pronounced in larger droplets. In droplets with diameter < 4 nm and high concentration of ions the charge of the ions is not compensated only by the solvent polarization charge but by the total charge that also includes the other free charge. This ﬁnding shows exceptions to the commonly made assumption that the solvent compensates the charge of the ions in solvents with very high dielectric constant. The study provides molecular insight into the bi-layer droplet structure assumed in the equilibrium partitioning model of C. Enke and assesses critical assumptions of the Iribarne-Thomson model for the ion-evaporation mechanism. <br></div>

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Understanding Conformational Entropy in Small Molecules

10.26434/chemrxiv.12671027 ◽

2020 ◽

Author(s):

Lucian Chan ◽

Garrett Morris ◽

Geoffrey Hutchison

Keyword(s):

Small Molecules ◽

Degrees Of Freedom ◽

Absolute Error ◽

Low Energy ◽

Standard Entropy ◽

Free Energies ◽

Conformational Entropy ◽

Wide Range ◽

High Degree ◽

Empirical Corrections

The calculation of the entropy of flexible molecules can be challenging, since the number of possible conformers grows exponentially with molecule size and many low-energy conformers may be thermally accessible. Different methods have been proposed to approximate the contribution of conformational entropy to the molecular standard entropy, including performing thermochemistry calculations with all possible stable conformations, and developing empirical corrections from experimental data. We have performed conformer sampling on over 120,000 small molecules generating some 12 million conformers, to develop models to predict conformational entropy across a wide range of molecules. Using insight into the nature of conformational disorder, our cross-validated physically-motivated statistical model can outperform common machine learning and deep learning methods, with a mean absolute error ≈4.8 J/mol•K, or under 0.4 kcal/mol at 300 K. Beyond predicting molecular entropies and free energies, the model implies a high degree of correlation between torsions in most molecules, often as- sumed to be independent. While individual dihedral rotations may have low energetic barriers, the shape and chemical functionality of most molecules necessarily correlate their torsional degrees of freedom, and hence restrict the number of low-energy conformations immensely. Our simple models capture these correlations, and advance our understanding of small molecule conformational entropy.

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Hydration Free Energies of Organic Molecules in the FreeSolv Database Calculated with Polarized Atom In Molecules Atomic Charges and the GAFF Force Field.

10.26434/chemrxiv.6015611.v1 ◽

2018 ◽

Author(s):

Maximiliano Riquelme ◽

Alejandro Lara ◽

David L. Mobley ◽

Toon Vestraelen ◽

Adelio R Matamala ◽

...

Keyword(s):

Force Field ◽

Functional Groups ◽

Electrostatic Interactions ◽

Organic Molecules ◽

Force Fields ◽

Chemical Elements ◽

Atomic Charges ◽

Free Energies ◽

Molecular Systems ◽

Solvent Model

<div>Computer simulations of bio-molecular systems often use force fields, which are combinations of simple empirical atom-based functions to describe the molecular interactions. Even though polarizable force fields give a more detailed description of intermolecular interactions, nonpolarizable force fields, developed several decades ago, are often still preferred because of their reduced computation cost. Electrostatic interactions play a major role in bio-molecular systems and are therein described by atomic point charges.</div><div>In this work, we address the performance of different atomic charges to reproduce experimental hydration free energies in the FreeSolv database in combination with the GAFF force field. Atomic charges were calculated by two atoms-in-molecules approaches, Hirshfeld-I and Minimal Basis Iterative Stockholder (MBIS). To account for polarization effects, the charges were derived from the solute's electron density computed with an implicit solvent model and the energy required to polarize the solute was added to the free energy cycle. The calculated hydration free energies were analyzed with an error model, revealing systematic errors associated with specific functional groups or chemical elements. The best agreement with the experimental data is observed for the MBIS atomic charge method, including the solvent polarization, with a root mean square error of 2.0 kcal mol<sup>-1</sup> for the 613 organic molecules studied. The largest deviation was observed for phosphor-containing molecules and the molecules with amide, ester and amine functional groups.</div>

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Partition Coefficients of Methylated DNA Bases Obtained from Free Energy Calculations with Molecular Electron Density Derived Atomic Charges.

10.26434/chemrxiv.5793996 ◽

2018 ◽

Author(s):

Alejandro Lara ◽

Maximiliano Riquelme ◽

Esteban Vöhringer-Martinez

Keyword(s):

Electron Density ◽

Partition Coefficients ◽

Dna Bases ◽

Atomic Charges ◽

Free Energies ◽

Solvation Model ◽

Minimal Basis ◽

Methylated Dna ◽

Implicit Solvation Model ◽

Good Agreement

<div> <div> <div> <p>Partition coefficients serve in various areas as pharmacology and environmental sciences to predict the hydrophobicity of different substances. Recently, they have been also used to address the accuracy of force fields for various organic compounds and specifically the methylated DNA bases. In this study atomic charges were derived by different partitioning methods (Hirshfeld and Minimal Basis Iterative Stockholder) directly from the electron density obtained by electronic structure calculations in vac- uum, with an implicit solvation model or with explicit solvation taking the dynamics of the solute and the solvent into account. To test the ability of these charges to describe electrostatic interactions in force fields for condensed phases the original atomic charges of the AMBER99 force field were replaced with the new atomic charges and combined with different solvent models to obtain the hydration and chloroform solvation free energies by molecular dynamics simulations. Chloroform-water partition coefficients derived from the obtained free energies were compared to experimental and previously reported values obtained with the GAFF or the AMBER-99 force field. The results show that good agreement with experimental data is obtained when the polarization of the electron density by the solvent has been taken into account deriving the atomic charges of polar DNA bases and when the energy needed to polarize the electron den- sity of the solute has been considered in the transfer free energy. These results were further confirmed by hydration free energies of polar and aromatic amino acid side chain analogues. Comparison of the two partitioning methods Hirsheld-I and Minimal Basis Iterative Stockholder (MBIS) revealed some deficiencies in the Hirshfeld-I method related to nonexistent isolated anionic nitrogen pro-atoms used in the method. Hydration free energies and partitioning coefficients obtained with atomic charges from the MBIS partitioning method accounting for polarization by the implicit solvation model are in good agreement with the experimental values. </p> </div> </div> </div>

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Molecular Docking Approaches to Suggest the Anti-Mycobacterial Targets of Natural Products

10.26434/chemrxiv.13325690.v1 ◽

2020 ◽

Author(s):

Rafael Baptista ◽

Sumana Bhowmick ◽

Shen Jianying ◽

Luis Mur

Keyword(s):

Natural Products ◽

Molecular Docking ◽

Free Energies ◽

Antibiotic Resistant ◽

Drug Lead ◽

Bisbenzylisoquinoline Alkaloids ◽

Docking Approach ◽

Global Threat ◽

Physicochemical And Structural Properties

Tuberculosis (TB) is a major global threat mostly due to the development of antibiotic resistant forms of Mycobacterium tuberculosis, the causal agent of the disease. Driven by the pressing need for new anti-mycobacterial agents, several natural products (NPs) have been shown to have in vitro activities against M. tuberculosis. The utility of any NP as a drug lead is augmented when the anti-mycobacterial target(s) is unknown. To suggest these, we used a molecular docking approach to predict the interactions of 53 selected anti-mycobacterial NPs against known ‘druggable’ mycobacterial targets ClpP1P2, DprE1, InhA, KasA, PanK, PknB and Pks13. The docking scores / binding free energies were predicted and calculated using AutoDock Vina along with physicochemical and structural properties of the NPs, using PaDEL descriptors. These were compared to the established inhibitor (control) drugs for each mycobacterial target. The specific interactions of the bisbenzylisoquinoline alkaloids 2-nortiliacorinine, tiliacorine and 13’-bromotiliacorinine against the targets PknB and DprE1 (-11.4, -10.9 and -9.8 kcal.mol-1 ; -12.7, -10.9 and -10.3 kcal.mol-1 , respectively) and the lignan αcubebin and Pks13 (-11.0 kcal.mol-1 ) had significantly superior docking scores compared to controls. Our approach can be used to suggest predicted targets for the NP to be validated experimentally but these in silico steps are likely to facilitate drug optimisation.

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SAMPL6 Octanol-Water Partition Coefficients from Alchemical Free Energy Calculations with MBIS Atomic Charges

10.26434/chemrxiv.9924806 ◽

2019 ◽

Author(s):

Maximiliano Riquelme ◽

Esteban Vöhringer-Martinez

Keyword(s):

Free Energy ◽

Electron Density ◽

Free Energy Calculations ◽

Basis Set ◽

Energetic Cost ◽

Atomic Charges ◽

Free Energies ◽

Energy Calculations ◽

Alchemical Free Energy ◽

Alchemical Free Energy Calculations

In molecular modeling the description of the interactions between molecules forms the basis for a correct prediction of macroscopic observables. Here, we derive atomic charges from the implicitly polarized electron density of eleven molecules in the SAMPL6 challenge using the Hirshfeld-I and Minimal Basis Set Iterative Stockholder(MBIS) partitioning method. These atomic charges combined with other parameters in the GAFF force field and different water/octanol models were then used in alchemical free energy calculations to obtain hydration and solvation free energies, which after correction for the polarization cost, result in the blind prediction of the partition coefficient. From the tested partitioning methods and water models the S-MBIS atomic charges with the TIP3P water model presented the smallest deviation from the experiment. Conformational dependence of the free energies and the energetic cost associated with the polarization of the electron density are discussed.

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Insights Studies for Certain Natural FDA Approved Polyphenolics and Repurposing for COVID-19

International Journal of Research in Pharmaceutical Sciences ◽

10.26452/ijrps.v11ispl1.3667 ◽

2020 ◽

Vol 11 (SPL1) ◽

pp. 1390-1395

Author(s):

Arafa Musa ◽

Ehab M. Mostafa ◽

Mohammad M. Al-Sanea ◽

Shaimaa R. Ahmed ◽

Gomaa Mostafa-Hedeab ◽

...

Keyword(s):

Docking Studies ◽

Human Populations ◽

Energy Score ◽

Protease Enzyme ◽

Human Disorders ◽

Variable Chemical ◽

Pancreatic Disorders ◽

New Treatment ◽

New Applications ◽

Death Cases

Natural polyphenolic drugs were approved for treatment of various diseases. Diosmin, rutin, quercetin, aesculin, genistein, hesperidin and silybin are known for their safety and have been applied for several human disorders including cancer, cardiovascular disorders, atherosclerosis, oxidative stress, capillary fragility, liver and pancreatic disorders and others. As the structures of the selected polyphenolic compounds possess variable chemical moieties with diverse chemical and electronic characters, these properties have been employed for further insights studies to predict new applications concerning the newly occurred pandemic. COVID-19 is a terrible disease that attacked millions of human populations at the end of year 2019. As the number of death cases has increased to exceed one million of humans, the early discovery of new treatment from previously approved and safe drugs is the main target of this study. Employing the putative docking studies for the selected polyphenolic drugs were done and the results were promising, all tested drugs exhibited high affinity with the selected five proteins of protease enzyme, the docking score ranged from -8.4461 to -26.1691 kcal/mol with 3-7 variable interaction bonds. Among the tested drugs, diosmin appeared as the most promising drug as it exhibited the highest energy score and interaction bonds with the most of proteins.

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