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1. Thermodynamics of ion binding and occupancy in potassium channels

   https://doi.org/10.1039/D1SC01887F  

   Jing, Zhifeng; Rackers, Joshua A.; Pratt, Lawrence R.; Liu, Chengwen; Rempe, Susan B.; Ren, Pengyu (June 2021, Chemical Science)

   Potassium channels modulate various cellular functions through efficient and selective conduction of K + ions. The mechanism of ion conduction in potassium channels has recently emerged as a topic of debate. Crystal structures of potassium channels show four K + ions bound to adjacent binding sites in the selectivity filter, while chemical intuition and molecular modeling suggest that the direct ion contacts are unstable. Molecular dynamics (MD) simulations have been instrumental in the study of conduction and gating mechanisms of ion channels. Based on MD simulations, two hypotheses have been proposed, in which the four-ion configuration is an artifact due to either averaged structures or low temperature in crystallographic experiments. The two hypotheses have been supported or challenged by different experiments. Here, MD simulations with polarizable force fields validated by ab initio calculations were used to investigate the ion binding thermodynamics. Contrary to previous beliefs, the four-ion configuration was predicted to be thermodynamically stable after accounting for the complex electrostatic interactions and dielectric screening. Polarization plays a critical role in the thermodynamic stabilities. As a result, the ion conduction likely operates through a simple single-vacancy and water-free mechanism. The simulations explained crystal structures, ion binding experiments and recent controversial mutagenesis experiments. This work provides a clear view of the mechanism underlying the efficient ion conduction and demonstrates the importance of polarization in ion channel simulations. 

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2. Computational study on the binding of Mango-II RNA aptamer and fluorogen using the polarizable force field AMOEBA

   https://doi.org/10.3389/fmolb.2022.946708  

   Yang, Xudong; Liu, Chengwen; Kuo, Yu-An; Yeh, Hsin-Chih; Ren, Pengyu (September 2022, Frontiers in Molecular Biosciences)

   Fluorescent light-up aptamers (FLAPs) are well-performed biosensors for cellular imaging and the detection of different targets of interest, including RNA, non-nucleic acid molecules, metal ions, and so on. They could be easily designed and emit a strong fluorescence signal once bound to specified fluorogens. Recently, one unique aptamer called Mango-II has been discovered to possess a strong affinity and excellent fluorescent properties with fluorogens TO1-Biotin and TO3-Biotin. To explore the binding mechanisms, computational simulations have been performed to obtain structural and thermodynamic information about FLAPs at atomic resolution. AMOEBA polarizable force field, with the capability of handling the highly charged and flexible RNA system, was utilized for the simulation of Mango-II with TO1-Biotin and TO3-Biotin in this work. The calculated binding free energy using published crystal structures is in excellent agreement with the experimental values. Given the challenges in modeling complex RNA dynamics, our work demonstrates that MD simulation with a polarizable force field is valuable for understanding aptamer-fluorogen binding and potentially designing new aptamers or fluorogens with better performance. 

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3. Coupled cluster theory in the condensed phase within the singles‐T density scheme for the environment response

   https://doi.org/10.1002/wcms.1463  

   Caricato, Marco (January 2020, WIREs Computational Molecular Science)

   Abstract Reliable simulations of molecules in condensed phase require the combination of an accurate quantum mechanical method for the core region, and a realistic model to describe the interaction with the environment. Additionally, this combination should not significantly increase the computational cost of the calculation compared to the corresponding in vacuo case. In this review, we describe the combination of methods based on coupled cluster (CC) theory with polarizable classical models for the environment. We use the polarizable continuum model (PCM) of solvation to discuss the equations, but we also show how the same theoretical framework can be extended to polarizable force fields. The theory is developed within the perturbation theory energy and singles‐T density (PTES) scheme, where the environmental response is computed with the CC single excitation amplitudes as an approximation for the full one‐particle reduced density. The CC‐PTES combination provides the best compromise between accuracy and computational effort for CC calculations in condensed phase, because it includes the response of the environment to the correlation density at the same computational cost of in vacuo CC. We discuss a number of numerical applications for ground and excited state properties, based on the implementation of CC‐PTES with single and double excitations (CCSD‐PTES), which show the reliability and computational efficiency of the method in reproducing experimental or full‐CC data. This article is characterized under:Electronic Structure Theory > Ab Initio Electronic Structure MethodsElectronic Structure Theory > Combined QM/MM MethodsSoftware > Quantum Chemistry 

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4. Water orientation and dynamics in the closed and open influenza B virus M2 proton channels

   https://doi.org/10.1038/s42003-021-01847-2  

   Gelenter, Martin D.; Mandala, Venkata S.; Niesen, Michiel J.; Sharon, Dina A.; Dregni, Aurelio J.; Willard, Adam P.; Hong, Mei (December 2021, Communications Biology)

   Abstract The influenza B M2 protein forms a water-filled tetrameric channel to conduct protons across the lipid membrane. To understand how channel water mediates proton transport, we have investigated the water orientation and dynamics using solid-state NMR spectroscopy and molecular dynamics (MD) simulations. 13 C-detected water 1 H NMR relaxation times indicate that water has faster rotational motion in the low-pH open channel than in the high-pH closed channel. Despite this faster dynamics, the open-channel water shows higher orientational order, as manifested by larger motionally-averaged 1 H chemical shift anisotropies. MD simulations indicate that this order is induced by the cationic proton-selective histidine at low pH. Furthermore, the water network has fewer hydrogen-bonding bottlenecks in the open state than in the closed state. Thus, faster dynamics and higher orientational order of water molecules in the open channel establish the water network structure that is necessary for proton hopping. 

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5. Dielectric continuum methods for quantum chemistry

   https://doi.org/10.1002/wcms.1519  

   Herbert, John M. (March 2021, WIREs Computational Molecular Science)

   Abstract This review describes the theory and implementation of implicit solvation models based on continuum electrostatics. Within quantum chemistry this formalism is sometimes synonymous with the polarizable continuum model, a particular boundary‐element approach to the problem defined by the Poisson or Poisson–Boltzmann equation, but that moniker belies the diversity of available methods. This work reviews the current state‐of‐the art, with emphasis on theory and methods rather than applications. The basics of continuum electrostatics are described, including the nonequilibrium polarization response upon excitation or ionization of the solute. Nonelectrostatic interactions, which must be included in the model in order to obtain accurate solvation energies, are also described. Numerical techniques for implementing the equations are discussed, including linear‐scaling algorithms that can be used in classical or mixed quantum/classical biomolecular electrostatics calculations. Anisotropic models that can describe interfacial solvation are briefly described. This article is categorized under:Electronic Structure Theory > Ab Initio Electronic Structure MethodsMolecular and Statistical Mechanics > Free Energy Methods 

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