Statistical Mechanics of Rotaxane Switches

A solution of rotaxane switches, which can switch their length by external stimuli, is described using statistical thermodynamics. We show that this solution can exhibit different behaviors. This solution can rapidly switch between isotropic and nematic liquid crystalline phases without altering temperature and concentration. There is a minimum of 13% length extension for which transition from pure isotropic to pure nematic phase is possible in idealistic system. We provided a framework to help synthetic chemists understand the requirements of switching efficiency, length change and concentration in rotaxane chemical design to create a macroscopic liquid crystalline phase change. When external rotaxane switches are depletants in the solution, length switching of rotaxane can significantly change the range and magnitude of colloid depletion interaction. This indicates a possible application of rotaxane switch in controlling colloid stability. We also investigate liquid crystalline behavior in solution of a rotaxane switches which change length to "adapt" to surrounding environment. We find the effect of adaptive length change on liquid crystalline behaviors is most dramatic at relatively low length extension

Correcting Density Functional Methods For Dispersion Interactions Using Pseudopotentials

The development of practical density functional theory (DFT) methods has provided the science community with a very important tool for modeling variety of systems such as materials, molecular and bio–molecular systems. Nonetheless, most practitioners of the method did not give enough attention to the deficiencies in modeling the dispersion interactions with the commonly used density functionals until a few years ago. Since then there have been many methods proposed to solve this problem and it is still a very active research area. I have tested a number of these dispersion–corrected DFT schemes for various systems that are of interest to our research group such as a water molecule interacting with a series of acenes and isomers of the water hexamer to see which of these methods give accurate results. Based on the tests, DFT–D3 of Grimme et al. and dispersion–corrected atom–centered pseudopotentials (DCACPs) attracted on our attention. DCACP procedure provided accurate interaction energies for the test cases, but the interaction energies fall too quickly as the distance between the molecules increases. I further investigated the effects of DCACPs on the employed density functionals with a detailed study of the interaction energies of isomers of the water hexamers and determined that with the original implementation it corrects for limitations of the BLYP functional in describing exchange-repulsion interaction as well as for dispersion interactions. We propose two different methods, namely DCACP+D and DCACP2, for improving the problems associated with the DCACP approach. These methods both provide improvements in the accuracy of the original DCACPs and also correct the quick fall-off problem of the interaction energies at long–range

New molecular simulation methods for quantitative modelling of protein-ligand interactions

The main theme of this work is the design and development of new molecular simulation protocols, to achieve more accurate and reliable estimates of free energy changes for processes relevant to the structure-based drug design. The works starts with an insight into the reproducibility problem for alchemical free energy calculations. Even if simulations are run with similar input files, the use of different simulation engines could give different free energy results. As part of a collaborative effort, the implementation details of AMBER, GROMACS, SOMD and CHARMM simulation codes were studied and free energy protocols for each software were validated to converge towards a reproducibility limit of about 0.20 kcal.mol-1 for hydration free energies of small organic molecules. Following, new simulation methods for the estimation of lipophilicity coefficients (log P and log D) for drug like molecules were developed and validated. log P values were computed for a dataset of 5 molecules with increasing fluorination level. Predictions were in line with the experimental measures and the simulations also allowed new insights into the water-solute interactions that drive the partitioning process. Then, as part of the SAMPL5 challenge, log D values for 53 drug-like molecules were computed. In this context two different simulation models were derived in order to take into account the presence of protonated species. The results were encouraging but also highlighted limits in alchemical free energy modelling. As an additional task of the SAMPL5 contest, three different protocols were validated for predicting absolute binding affinities for 22 host-guest systems. The first model yielded a free energy of binding based on free energy changes in solvated and complex phase; the second added the long range dispersion correction to the previous model; the third one used a standard state correction term. All three protocols were among the top-ranked submission in SAMPL5, with a correlation coefficient R2 of about 0.7 against experimental data. Finally, the origins and magnitude of the finite size artefacts in alchemical free energy calculations were investigated. Finite size artefacts are especially predominant in calculations that involve changes in the net-charge of a solute. A new correction scheme was devised for the Barker Watts Reaction Field approach and compared with the literature. Hydration free energy calculations on simple ionic species were carried out to validate the consistency of the scheme and the approach was further extended to host-guest binding affinities predictions

How Detergent Impacts Membrane Proteins: Atomic-Level Views of Mitochondrial Carriers in Dodecylphosphocholine

Characterizing the structure of membrane proteins (MPs) generally requires extraction from their native environment, most commonly with detergents. Yet, the physicochemical properties of detergent micelles and lipid bilayers differ markedly and could alter the structural organization of MPs, albeit without general rules. Dodecylphosphocholine (DPC) is the most widely used detergent for MP structure determination by NMR, but the physiological relevance of several prominent structures has been questioned, though indirectly, by other biophysical techniques, e.g., functional/thermostability assay (TSA) and molecular dynamics (MD) simulations. Here, we resolve unambiguously this controversy by probing the functional relevance of three different mitochondrial carriers (MCs) in DPC at the atomic level, using an exhaustive set of solution-NMR experiments, complemented by functional/TSA and MD data. Our results provide atomic-level insight into the structure, substrate interaction and dynamics of the detergent−membrane protein complexes and demonstrates cogently that, while high-resolution NMR signals can be obtained for MCs in DPC, they systematically correspond to nonfunctional states

Conformational transitions of the serotonin 5-HT3 receptor

International audienceThe serotonin 5-HT3 receptor is a pentameric ligand-gated ion channel (pLGIC). It belongs to a large family of receptors that function as allosteric signal transducers across the plasma membrane1,2; upon binding of neurotransmitter molecules to extracellular sites, the receptors undergo complex conformational transitions that result in transient opening of a pore permeable to ions. 5-HT3 receptors are therapeutic targets for emesis and nausea, irritable bowel syndrome and depression3. In spite of several reported pLGIC structures4-8, no clear unifying view has emerged on the conformational transitions involved in channel gating. Here we report four cryo-electron microscopy structures of the full-length mouse 5-HT3 receptor in complex with the anti-emetic drug tropisetron, with serotonin, and with serotonin and a positive allosteric modulator, at resolutions ranging from 3.2 Å to 4.5 Å. The tropisetron-bound structure resembles those obtained with an inhibitory nanobody5 or without ligand9. The other structures include an 'open' state and two ligand-bound states. We present computational insights into the dynamics of the structures, their pore hydration and free-energy profiles, and characterize movements at the gate level and cation accessibility in the pore. Together, these data deepen our understanding of the gating mechanism of pLGICs and capture ligand binding in unprecedented detail