Showing papers by "Stephen J. Tucker published in 2023"
TL;DR: In this paper , the binding free energies for different anions to the synthetic ionophore, biotin[6]uril hexamethyl ester in acetonitrile and to biotin hexaacid in water by employing non-polarizable and polarizable force fields were calculated.
Abstract: Transmembrane anion transport by synthetic ionophores has received increasing interest not only because of its relevance for understanding endogenous anion transport, but also because of potential implications for therapeutic routes in disease states where chloride transport is impaired. Computational studies can shed light on the binding recognition process and can deepen our mechanistic understanding of them. However, the ability of molecular mechanics methods to properly capture solvation and binding properties of anions is known to be challenging. Consequently, polarizable models have been suggested to improve the accuracy of such calculations. In this study, we calculate binding free energies for different anions to the synthetic ionophore, biotin[6]uril hexamethyl ester in acetonitrile and to biotin[6]uril hexaacid in water by employing non-polarizable and polarizable force fields. Anion binding shows strong solvent dependency consistent with experimental studies. In water, the binding strengths are iodide > bromide > chloride, and reversed in acetonitrile. These trends are well captured by both classes of force fields. However, the free energy profiles obtained from potential of mean force calculations and preferred binding positions of anions depend on the treatment of electrostatics. Results from simulations using the AMOEBA force-field, which recapitulate the observed binding positions, suggest strong effects from multipoles dominate with a smaller contribution from polarization. The oxidation status of the macrocycle was also found to influence anion recognition in water. Overall, these results have implications for the understanding of anion host interactions not just in synthetic ionophores, but also in narrow cavities of biological ion channels.
TL;DR: In this paper , a class of biologics based on VHH domains (nanobodies) can achieve far greater selectivity as both activators and inhibitors of TREK-2 channel function and can differentiate individual members of this family.
TL;DR: In this article , the authors use non-Markovian equations (i.e., offer a general description that includes the MSM as a particular case) to develop a relatively simple analytical model that describes the non-equilibrium behavior of the temperature-sensitive TRP ion channels, TRPV1 and TRPM8.
Abstract: The Markov state model (MSM) is a popular theoretical tool for describing the hierarchy of time scales involved in the function of many proteins especially ion channel gating. A MSM is a particular case of the general non-Markovian model, where the rate of transition from one state to another does not depend on the history of state occupancy within the system, i.e., it only includes reversible, non-dissipative processes. However, this requires knowledge of the precise conformational state of the protein and is not predictive when those details are not known. In the case of ion channels, this simple description fails in real (non-equilibrium) situations, for example when local temperature changes, or when energy losses occur during channel gating. Here, we show it is possible to use non-Markovian equations (i.e. offer a general description that includes the MSM as a particular case) to develop a relatively simple analytical model that describes the non-equilibrium behavior of the temperature-sensitive TRP ion channels, TRPV1 and TRPM8. This model accurately predicts asymmetrical opening and closing rates, infinite processes, and the creation of new states, as well as the effect of temperature changes throughout the process. This approach therefore overcomes the limitations of the MSM and allows us to go beyond a mere phenomenological description of the dynamics of ion channel gating towards a better understanding of the physics underlying these processes. Significance Statement Modeling ion channel processes has long relied on the Markovian assumption. However, Markov theory cannot translate situations in which the physical state of an ion channel changes during its gating process. By using a non-Markovian approach, we develop a simple analytical model that describes the non-equilibrium behavior of two temperature-sensitive TRP channels, TRPV1 and TRPM8. This model accurately describes and predicts their biophysical behavior as well as their temperature dependence. This approach therefore provides a better understanding of the physics underlying dynamic conformational changes such as those that occur during ion channel gating.
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TL;DR: In this paper , the limitations of non-polarizable force fields in describing anion binding poses in nonpolar synthetic hosts were discussed. But the authors did not consider the effect of the force field on the anion bounding pose.
Abstract: Correction for 'Limitations of non-polarizable force fields in describing anion binding poses in non-polar synthetic hosts' by David Seiferth et al., Phys. Chem. Chem. Phys., 2023, 25, 17596-17608, https://doi.org/10.1039/D3CP00479A.
TL;DR: In this paper , a chloride-pumping rhodopsin (ClR) was used as an example of a ClR-selective protein known to contain a defined binding site composed predominantly of hydrophobic residues.
TL;DR: In this paper , a chloride-pumping rhodopsin (ClR) was used as an example of a membrane protein known to contain a defined anion binding site composed predominantly of hydrophobic residues.
Abstract: The functional properties of some biological ion channels and membrane transport proteins are proposed to exploit anion-hydrophobic interactions. Here, we investigate a chloride-pumping rhodopsin (ClR) as an example of a membrane protein known to contain a defined anion binding site composed predominantly of hydrophobic residues. Using molecular dynamics simulations, we explore Cl− binding to this hydrophobic site and compare the dynamics arising when electronic polarization is neglected (CHARMM36 (c36) fixed-charge force field), included implicitly (via the prosECCo force field), or included explicitly (through the polarizable force field, AMOEBA). Free energy landscapes of Cl− moving out of the binding site and into bulk solution demonstrate that the inclusion of polarization results in stronger ion binding and a second metastable binding site in ClR. Simulations focused on this hydrophobic binding site also indicate longer binding durations and closer ion proximity when polarization is included. Furthermore, simulations reveal that Cl− within this binding site interacts with an adjacent loop to facilitate rebinding events that are not observed when polarization is neglected. These results demonstrate how the inclusion of polarization can influence the behavior of anions within protein binding sites and thereby reveal novel mechanisms. Statement of Significance Molecular simulations based on classical (Newtonian) mechanics represent the most common method of visualizing the behavior of water and ions within channels and nanopores. Although computationally efficient, many of the approximations required mean that these simulations often do not fully capture the complex and dynamic interactions involved. Here, we use the prosECCo force field that offers an improved electronic description whilst maintaining computational efficiency. We show that using this method to include the effects of polarization greatly influences the binding dynamics of anions to a protein binding site and yields results similar to more accurate but computationally demanding methods.