Potentials of mean force in acidic proton transfer reactions in constrained geometries

Free energy barriers associated with the transfer of an excess proton in water and related to the potentials of mean force in proton transfer episodes have been computed in a wide range of thermodynamic states, from low-density amorphous ices to high-temperature liquids under the critical point for unconstrained and constrained systems. The latter were represented by set-ups placed inside hydrophobic graphene slabs at the nanometric scale allocating a few water layers, namely one or two in the narrowest case. Water–proton and carbon–proton forces were modelled with a Multi-State Empirical Valence Bond method. As a general trend, a competition between the effects of confinement and temperature is observed on the local hydrogen-bonded structures around the lone proton and, consequently, on the mean force exerted by its environment on the water molecule carrying the proton. Free energy barriers estimated from the computed potentials of mean force tend to rise with the combined effect of increasing temperatures and the packing effect due to a larger extent of hydrophobic confinement. The main reason observed for such enhancement of the free energy barriers was the breaking of the second coordination shell around the lone proton.Postprint (author's final draft

Free-energy surfaces of ionic adsorption in cholesterol-free and cholesterol-rich phospholipid membranes

Free energy surfaces associated to the adsorption of metal cations ((Formula presented.), (Formula presented.), (Formula presented.), and (Formula presented.)) in biological environments have been computed by metadynamics simulations. In all cases, the systems were modelled using the CHARMM36 force field. The free-energy landscapes unveil specific binding behaviour of metal cations. So, (Formula presented.) and (Formula presented.) are more likely to stay in the aqueous solution, and can easily bind to a few lipid oxygens by overcoming low free-energy barriers. Differently, (Formula presented.) is most stable when bound to four lipid oxygens of the membranes, rather than being hydrated in the aqueous solution. Finally, (Formula presented.) is tightly hydrated, and can hardly lose a hydration water and bind directly to the membranes. When cholesterol is included inside the membrane at concentration up to 50%, the resulting free-energy landscapes reveal the competition between binding of sodium to water and to lipid head groups, although the binding competitiveness of lipid head groups is diminished by cholesterol contents. When cholesterol concentration is greater than 30%, the ionic binding is significantly reduced, which coincides with the phase transition point of DMPC-cholesterol membranes from a liquid-disordered phase to a liquid-ordered phase.Postprint (author's final draft

Structure and dynamics of water at carbon-based interfaces

Water structure and dynamics are affected by the presence of a nearby interface. Here, first we review recent results by molecular dynamics simulations about the effect of different carbon-based materials, including armchair carbon nanotubes and a variety of graphene sheets—flat and with corrugation—on water structure and dynamics. We discuss the calculations of binding energies, hydrogen bond distributions, water’s diffusion coefficients and their relation with surface’s geometries at different thermodynamical conditions. Next, we present new results of the crystallization and dynamics of water in a rigid graphene sieve. In particular, we show that the diffusion of water confined between parallel walls depends on the plate distance in a non-monotonic way and is related to the water structuring, crystallization, re-melting and evaporation for decreasing inter-plate distance. Our results could be relevant in those applications where water is in contact with nanostructured carbon materials at ambient or cryogenic temperatures, as in man-made superhydrophobic materials or filtration membranes, or in techniques that take advantage of hydrated graphene interfaces, as in aqueous electron cryomicroscopy for the analysis of proteins adsorbed on graphene.Postprint (author's final draft

Multistate empirical valence bond study of temperature and confinement effects on proton transfer in water inside hydrophobic nanochannels

Microscopic characteristics of an aqueous excess proton in a wide range of thermodynamic states, from low density amorphous ices (down to 100 K) to high temperature liquids under the critical point (up to 600 K), placed inside hydrophobic graphene slabs at the nanometric scale (with interplate distances between 3.1 and 0.7 nm wide) have been analyzed by means of molecular dynamics simulations. Water-proton and carbon-proton forces were modeled with a multistate empirical valence bond method. Densities between 0.07 and 0.02 1/Å^3 have been considered. As a general trend, we observed a competition between effects of confinement and temperature on structure and dynamical properties of the lone proton. Confinement has strong influence on the local structure of the proton, whereas the main effect of temperature on proton properties is observed on its dynamics, with significant variation of proton transfer rates, proton diffusion coefficients, and characteristic frequencies of vibrational motions. Proton transfer is an activated process with energy barriers between 1 and 10 kJ/mol for both proton transfer and diffusion, depending of the temperature range considered and also on the interplate distance. Arrhenius-like behavior of the transfer rates and of proton diffusion are clearly observed for states above 100 K. Spectral densities of proton species indicated that in all states Zundel-like and Eigen-like complexes survive at some extent.Postprint (author's final draft

Dynamical aspects of intermolecular proton transfer in liquid water and low-density amorphous ices

The microscopic dynamics of an excess proton in water and in low-density amorphous ices has been studied by means of a series of molecular dynamics simulations. Interaction of water with the proton species was modelled using a multistate empirical valence bond Hamiltonian model. The analysis of the effects of low temperatures on proton diffusion and transfer rates has been considered for a temperature range between 100 and 298 K at the constant density of 1 g cm -3 . We observed a marked slowdown of proton transfer rates at low temperatures, but some episodes are still seen at 100 K. In a similar fashion, mobility of the lone proton gets significantly reduced when temperature decreases below 273 K. The proton transfer in low-density amorphous ice is an activated process with energy barriers between 1–10 kJ/mol depending of the temperature range considered and eventually showing Arrhenius-like behavior. Spectroscopic data indicated the survival of both Zundel and Eigen structures along the whole temperature range, revealed by significant spectral frequency shifts.Postprint (published version

In silico drug design of benzothiadiazine derivatives interacting with phospholipid cell membranes

The use of drugs derived from benzothiadiazine, a bicyclic heterocyclic benzene derivative, has become a widespread treatment for diseases such as hypertension, low blood sugar or the human immunodeficiency virus, among others. In this work we have investigated the interactions of benzothiadiazine and four of its derivatives designed in silico with model zwitterionic cell membranes formed by dioleoylphosphatidylcholine, 1,2-dioleoyl-sn-glycero-3-phosphoserine and cholesterol at the liquid–crystal phase inside aqueous potassium chloride solution. We have elucidated the local structure of benzothiadiazine by means of microsecond molecular dynamics simulations of systems including a benzothiadiazine molecule or one of its derivatives. Such derivatives were obtained by the substitution of a single hydrogen site of benzothiadiazine by two different classes of chemical groups, one of them electron-donating groups (methyl and ethyl) and another one by electron-accepting groups (fluorine and trifluoromethyl). Our data have revealed that benzothiadiazine derivatives have a strong affinity to stay at the cell membrane interface although their solvation characteristics can vary significantly and they can be fully solvated by water in short periods of time or continuously attached to specific lipid sites during intervals of 10–70 ns. Furthermore, benzothiadiazines are able to bind lipids and cholesterol chains by means of single and double hydrogen-bonds of characteristic lengths between 1.6 and 2.1 Å.Postprint (author's final draft

Long-lasting salt bridges provide the anchoring mechanism of oncogenic kirsten rat sarcoma proteins at cell membranes

RAS proteins work as GDP-GTP binary switches and regulate cytoplasmic signaling networks that are able to control several cellular processes, playing an essential role in signal transduction pathways involved in cell growth, differentiation, and survival, so that overacting RAS signaling can lead to cancer. One of the hardest challenges to face is the design of mutation-selective therapeutic strategies. In this work, a G12D-mutated farnesylated GTP-bound Kirsten RAt sarcoma (KRAS) protein has been simulated at the interface of a DOPC/DOPS/cholesterol model anionic cell membrane. A specific long-lasting salt bridge connection between farnesyl and the hypervariable region of the protein has been identified as the main mechanism responsible for the binding of oncogenic farnesylated KRAS-4B to the cell membrane. Free-energy landscapes allowed us to characterize local and global minima of KRAS-4B binding to the cell membrane, revealing the main pathways between anchored and released states.Postprint (published version

Molecular dynamics of di-palmitoyl-phosphatidyl-choline biomembranes in ionic solution: adsorption of the precursor neurotransmitter tryptophan

Microscopic structure of a fully hydrated di-palmytoil-phosphatidyl-choline lipid bilayer membrane in the liquid-crystalline phase has been analyzed with all-atom molecular dynamics simulations based on the recently parameterized CHARMM36 force field. Within the membrane, a single molecule of the a-aminoacid tryptophan (precursor of important neurotransmitters such as serotonin and melatonin) has been embedded and its structure and binding sites to water and lipids have been explored. In addition, properties such as radial distribution functions, hydrogen-bonding, energy and pressure profiles and the potentials of mean force of water-tryptophan and lipid-tryptophan have been evaluated. It has been observed that tryptophan usually has a tendency to place itself close to the lipid headgroups but that it can be fully hydrated during short time intervals of the order of a few nanoseconds. This would indicate that, for tryptophan, both hydrophobic forces as well as the attraction to polar sites of the lipids play a significant role in the definition of its structure and binding states.Postprint (author's final draft

Cellular absorption of small molecules: free energy landscapes of melatonin binding at phospholipid membranes

Free energy calculations are essential to unveil mechanisms at the atomic scale such as binding of small solutes and their translocation across cell membranes, eventually producing cellular absorption. Melatonin regulates biological rhythms and is directly related to carcinogenesis and neurodegenerative disorders. Free energy landscapes obtained from well-tempered metadynamics simulations precisely describe the characteristics of melatonin binding to specific sites in the membrane and reveal the role of cholesterol in free energy barrier crossing. A specific molecular torsional angle and the distance between melatonin and the center of the membrane along the normal to the membrane Z-axis have been considered as suitable reaction coordinates. Free energy barriers between two particular orientations of the molecular structure (folded and extended) have been found to be of about 18¿kJ/mol for z-distances of about 1–2¿nm. The ability of cholesterol to expel melatonin out of the internal regions of the membrane towards the interface and the external solvent is explained from a free energy perspective. The calculations reported here offer detailed free energy landscapes of melatonin embedded in model cell membranes and reveal microscopic information on its transition between free energy minima, including the location of relevant transition states, and provide clues on the role of cholesterol in the cellular absorption of small molecules.Peer ReviewedPostprint (published version

Binding free energies of small-molecules in phospholipid membranes: aminoacids, serotonin and melatonin

Free energy barriers associated to the binding of small-molecules at phospholipid zwitterionic membranes have been computed at 323 K for a variety of species: tryptophan, histidine, tyrosine, serotonin and melatonin bound to a model membrane formed by di-palmitoyl-phosphatidyl-choline lipids inside aqueous sodium chloride solution. We have computed the radial distribution functions of all species for a variety of membrane and water related sites and extracted potentials of mean force through the reversible work theorem. In all cases but histidine, the molecular probes are able to either be fully solvated by water or be embedded into the interface of the membrane. Our results indicate that binding of all species to water corresponds to free energy barriers of heights between 0.2 and 1.75 kcal/mol. Free energy barriers of association of small-molecules to lipid chains range between 0.6 and 3.1 kcal/mol and show different characteristics: all species but histidine are most likely bound to oxygens belonging to the phosphate and to the glycerol groups. Histidine shows a clear preference to be fully solvated by water whereas the aqueous solvation of serotonin is the less likely case of them all. No free permeation through the membrane of any small-molecule has been observed during the time span of the simulation experiments.Preprin