Browsing by Subject "Hydrophobicity"

Now showing 1 - 3 of 3

An improved method for predicting logP
(2006-08) Wu, Yubin, 1976-; Pearlman, Robert S.
The logarithm of the octanol/water partition coefficient (logP) is used extensively as an indicator of hydrophobicity or lipophilicity within quantitative structure-activity relationships (QSARs) in the pharmaceutical, environmental, and other chemistry-related sciences. LogP is an important component of Lipinki’s “rule of 5” which is used throughout pharmaceutical industry to distinguish “drug-like” compounds from those likely to exhibit poor bioavailability. Using structure-based, calculated predictions of logP, rather than experimentally measured values, is of obvious advantage given the nearinfinite number of potential drug compounds and the relatively small number of compounds for which logP has been measured. MlogP is a simple yet useful structurebased method developed by Moriguchi et al. to estimate logP values. Moriguchi established rules for dividing molecular structures into 13 types of “fragments” and used measured logP values for 1,230 compounds to develop a regression equation based the frequencies with which each fragment occurred in the structure of each compound. Regrettably, Moriguchi’s description of his method is unclear in several respects. Lipinski implemented a program to calculate MlogP values but was forced to make certain assumptions regarding fragment definitions, etc. We will present a revised and definitive algorithm based on Moriguchi’s original concepts but developed using far more robust fragment definitions and statistical methods. The improved algorithm yields significantly better estimates for 6,529 “STARLIST” compounds with experimentally measured logP values.
Solvation of nanoscale interfaces
(2010-05) Kapcha, Lauren Helene; Rossky, Peter J.; Henkelman, Graeme; Johnston, Keith P.; Makarov, Dmitrii E.; Stevenson, Keith J.
A dehydrogen is an ‘under-wrapped’ hydrogen bond in a protein that is purported to be a hot spot for binding due to the favorable replacement of water with hydrocarbon upon binding of another protein. A model at the level of dielectric constants is used to test the validity of the claim that moving a hydrogen bond from high dielectric (i.e. a dehydron) to low dielectric (i.e. after binding of another protein) is actually a thermodynamically favorable process. In simulation, several proteins have been shown to undergo a dewetting transition when fixed components are separated a small distance. A new atomic-level hydrophobicity scale is combined with topographical information to characterize protein interfaces. The relationship between hydrophobicity and topography for protein surfaces known to be involved in binding is examined. This framework is then applied to identify surface characteristics likely to have an affect on the occurrence of a dewetting transition. Cadmium selenide (CdSe) nanoparticles form nanospheres or nanorods when grown in solutions of varying concentrations of the surfactants hexylphosphonic acid (HPA) and trioctylphosphine oxide (TOPO). Relative binding free energies are calculated for HPA and TOPO to the solvent-accessible faces of CdSe crystals. Binding free energies calculated with a Molecular Mechanics-Generalized Born model are used to identify a set of low free energy structures for which the solvation free energy is refined with the solution to the Poisson equation. These relative binding free energies provide information about the relative growth rates of these crystal faces in the presence of surfactants. Relative growth rates are then used to help understand why nanoparticles form certain shapes in the presence of specific surfactants.
Statistical thermodynamics of solvophobic solvation in water and simpler liquids
(2011-12) Dowdle, John Robert; Rossky, Peter J.; Truskett, Thomas M.; Ganesan, Venkat; Mullins, Charles B.; Makarov, Dmitrii E.
Temperature, pressure, and length scale dependence of the solvation of simple solvophobic solutes is investigated in the Jagla liquid, a simple liquid consisting of particles that interact via a spherically symmetric potential combining hard and soft core interactions. The results are compared with identical calculations for a model of a typical atomic liquid, the Lennard-Jones (LJ) potential, and with predictions for hydrophobic solvation in water using the recently developed cavity equation of state and the extended simple point charge model. We find that the Jagla liquid captures the qualitative thermodynamic behavior of hydrophobic hydration as a function of temperature and pressure for both small and large length scale solutes. In particular, for both the Jagla liquid and water, we observe temperature-dependent enthalpy and entropy of solvation for all solute sizes as well as a negative solvation entropy for sufficiently small solutes at low temperature. This feature of water-like solvation is distinct from the strictly positive and temperature independent enthalpy and entropy of cavity solvation observed in the Lennard-Jones fluid. The results suggest that a competition between two energy scales that favors low-density, open structures as temperature is decreased is an essential interaction of a liquid that models hydrophobic hydration. In addition the Jagla liquid dewets surfaces of large radii of curvature less readily than the Lennard-Jones liquid, and the so-called ``length scale crossover'' in solvation, whereby solvation free energies change from scaling with the solute volume to scaling with the solute surface area, occurs at length scales that are larger relative to the solvent size. Both features reflect a greater flexibility or elasticity in the Jagla liquid structure than that of a typical liquid, similar to water's ability to maintain its hydrogen bond network. The implications of the differences in crossover behavior between water-like and typical liquids are examined in the context of a simple thought experiment on the aggregation of solvophobic solutes that builds on ideas from Chandler and Rajamani et al. We find that water-like crossover behavior exposes a size range of solvophobic aggregates to destabilization upon cooling and pressurizing, which may thereby precipitate phenomena such as cold and pressure denaturation of proteins. Statistics of density fluctuations, void space, and pair distributions are analyzed for molecular-scale volumes. The pair distribution functions are used to provide an estimate of the size of the Jagla particle with a physical basis. The void distributions are observed to be distinct in the three liquids, with low temperature distributions in the LJ and Jagla liquids demonstrating a high degree of skewness. The void distributions observed in LJ liquid are hard sphere-like, while those of water and the Jagla liquid exhibit a higher degree of density inhomogeneity relative to a hard sphere system. The well-known Gaussian behavior of density fluctuations in molecular volumes in water is not generally observed in other liquids, as evidenced by the fact that this behavior is not consistently observed in either the LJ or the Jagla liquids. An exploratory study of the effects of explicit solvent on the sequence energy landscape of model heteropolymers has been performed. For a fixed set of configurations, the energy landscape of all possible sequences taken from a two letter alphabet consisting of only solvophilic and solvophobic monomers is characterized at different solvent temperatures. Non-trivial solvent and temperature effects are manifest in the distribution of sequences, confirming that the negation of these effects may have profound consequences on designability.