Here we present an evaluation of the binding affinity prediction accuracy of the free energy calculation method FEP+ on internal active drug discovery projects and on a large new public benchmark set. File list (3) download file view on ChemRxiv manuscript.pdf (4.23 MiB) download file view on ChemRxiv supplementary.pdf (0.92 MiB) download file view on ChemRxiv tables.zip (5.99 KiB)

We have carried out molecular dynamics simulations of model polymer–nanoparticle composites (PNCs) consisting of coarse-grained bead-necklace polymer chains and roughly spherical nanoparticles comprised of like beads for the purpose of gaining understanding of the influence of the nanoparticle–polymer interface on the viscoelastic properties of PNCs. The dynamic shear modulus Gc(t) and viscosity ηc of the PNCs were determined as a function of nanoparticle volume fraction, specific nanoparticle–polymer interfacial area, and the nature of the nanoparticle–polymer interaction. The viscoelastic properties of the PNCs were well described as a product of a polymer matrix dynamic shear modulus or viscosity and a particle volume fraction dependent effect independent of particle size, analogous to treatments of conventional particle composites. In contrast to many conventional composites, however, the viscoelastic properties of the polymer matrix were strongly perturbed by the nanoparticles and depended upon the nature of the nanoparticle–polymer interactions.

To investigate the implications of the unique properties of fullerenes on their interaction with and passive transport into lipid membranes, atomistic molecular dynamics simulations of a C60 fullerene in a fully hydrated di-myristoyl-phoshatidylcholine lipid membrane have been carried out. In these simulations the free energy and the diffusivity of the fullerene were obtained as a function of its position within the membrane. These properties were utilized to calculate the permeability of fullerenes through the lipid membrane. Simulations reveal that the free energy decreases as the fullerene passes from the aqueous phase, through the head group layer and into the hydrophobic core of the membrane. This decrease in free energy is not due to hydrophobic interactions but rather to stronger van der Waals (dispersion) interactions between the fullerene and the membrane compared to those between the fullerene and (bulk) water. It was found that there is no free energy barrier for transport of a fullerene from the aqueous phase into the lipid core of the membrane. In combination with strong partitioning of the fullerenes into the lipidic core of the membrane, this "barrierless" penetration results in an astonishingly large permeability of fullerenes through the lipid membrane, greater than observed for any other known penetrant. When the strength of the dispersion interactions between the fullerene and its surroundings is reduced in the simulations, thereby emulating a nanometer sized hydrophobic particle, a large free energy barrier for penetration of the head group layer emerges, indicating that the large permeability of fullerenes through lipid membranes is a result of their unique interaction with their surrounding medium.

Molecular-dynamics simulations of a single C(60) fullerene and pairs of C(60) fullerenes in aqueous solution have been performed for the purpose of obtaining improved understanding of the nature of solvent-induced interactions between C(60) fullerenes in water. Our simulations reveal repulsive solvent-induced interactions between two C(60) fullerenes in aqueous solution in contrast to the associative effects observed for conventional nonpolar solutes. A decomposition of the solvent-induced potential of mean force between fullerenes into entropy and energy (enthalpy) contributions reveals that the water-induced repulsion between fullerenes is energetic in origin, contrasting strongly to entropy-driven association observed for conventional nonpolar solutes. The dominance of energy in the solvent-induced interactions between C(60) fullerenes arises primarily from the high atomic density of the C(60) molecule, resulting in strong C(60)-water van der Waals attraction that is reduced upon association of the fullerenes. The water-induced repulsion is found to decrease with increasing temperature due largely to an increasing contribution from a relatively weak entropy-driven association.

Molecular dynamics simulations were carried out in order to study the hydration of C60 fullerenes, carbon nanotubes, and graphene sheets in aqueous solution and the nature of water-induced interactions between these carbon nanoparticles. The hydration of these nonpolar carbon nanoparticles does not exhibit classical hydrophobic character due to the high density of surface atoms (carbon) resulting in strong water-surface dispersion interactions. Water was found to wet the nanoparticle surfaces independent of nanoparticle surface curvature, with the decrease in the extent of water-water hydrogen bonding with decreasing surface curvature being offset by stronger water-surface interactions. While all carbon nanoparticles investigated are anticipated to aggregate in water due to strong direct nanoparticle-nanoparticle interactions, the water-induced interactions between nanoparticles were found to be repulsive and, in contrast to the wetting behavior, were observed to exhibit strong dependence on surface curvature. The strength of the water-induced interaction between carbon nanoparticles was found to correlate well with the number of hydration water molecules displaced upon particle aggregation, which, relative to the amount of direct nanoparticle-nanoparticle contact engendered upon aggregation, decreases with decreasing surface curvature.