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Cation–π interactions play important roles in molecular recognition and in the stability and function of proteins. However, accurate description of the structure and energetics of cation–π interactions presents a challenge to both additive and polarizable force fields, which are rarely designed to account for the complexation of charged groups with aromatic moieties. We calibrate the Drude polarizable force field for complexes of alkali metal ions (Li+, Na+, K+, Rb+, Cs+), ammonium (NH4+), tetramethylammonium (TMA+), and tetraethylammonium (TEA+) with aromatic amino acid side chain model compounds (benzene, toluene, 4‐methylphenol, 3‐methylindole) using high‐level ab initio quantum chemical properties of these complexes. Molecular dynamics simulations reveal that cation–π complexes of the hard and tightly coordinated Li+ and Na+ ions are not stable in water but that larger ions form stable complexes, with binding free energies ranging between −0.8 and −2.9 kcal/mol. Like in gas phase, all complexes at equilibrium adopt an "en‐face" complexation mode in water. The optimized Drude polarizable model provides an accurate description of the cation–π interactions involving small ions and proteins. © 2019 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]

Cation-π interactions play important roles in the stabilization of protein structures and protein-ligand complexes. They contribute to the binding of quaternary ammonium ligands (mainly RNH3+ and RN(CH3)3+) to various protein receptors and are likely involved in the blockage of potassium channels by tetramethylammonium (TMA+) and tetraethylammonium (TEA+). Polarizable molecular models are calibrated for NH4+, TMA+, and TEA+ interacting with benzene, toluene, 4-methylphenol, and 3-methylindole (representing aromatic amino acid side chains) based on the ab initio MP2(full)/6-311++G(d,p) properties of the complexes. Whereas the gas-phase affinity of the ions with a given aromatic follows the trend NH4+ > TMA+ > TEA+, molecular dynamics simulations using the polarizable models show a reverse trend in water, likely due to a contribution from the hydrophobic effect. This reversed trend follows the solubility of aromatic hydrocarbons in quaternary ammonium salt solutions, which suggests a role for cation-π interactions in the salting-in of aromatic compounds in solution. Simulations in water show that the complexes possess binding free energies ranging from -1.3 to -3.3 kcal/mol (compared to gas-phase binding energies between -8.5 and -25.0 kcal/mol). Interestingly, whereas the most stable complexes involve TEA+ (the largest ion), the most stable solvent-separated complexes involve TMA+ (the intermediate-size ion). [ABSTRACT FROM AUTHOR]

Summary In human cells, membrane proteins of the rhesus (Rh) family excrete ammonium and play a role in pH regulation. Based on high-resolution structures, Rh proteins are generally understood to act as NH 3 channels. Given that cell membranes are permeable to gases like NH 3 , the role of such proteins remains a paradox. Using molecular and quantum mechanical calculations, we show that a crystallographically identified site in the RhCG pore actually recruits NH 4 + , which is found in higher concentration and binds with higher affinity than NH 3 , increasing the efficiency of the transport mechanism. A proton is transferred from NH 4 + to a signature histidine (the only moiety thermodynamically likely to accept a proton) followed by the diffusion of NH 3 down the pore. The excess proton is circulated back to the extracellular vestibule through a hydrogen bond network, which involves a highly conserved and functionally important aspartic acid, resulting in the net transport of NH 3 . [ABSTRACT FROM AUTHOR]

Proteins of the Amt/MEP family facilitate ammonium transport across the membranes of plants, fungi, and bacteria and are essential for growth in nitrogen-poor environments. Some are known to facilitate the diffusion of the neutral NH3, while others, notably in plants, transport the positively charged NH4+. On the basis of the structural data for AmtB from Escherichia coli, we illustrate the mechanism by which proteins from the Amt family can sustain electrogenic transport. Free energy calculations show that NH4+ is stable in the AmtB pore, reaching a binding site from which it can spontaneously transfer a proton to a pore-lining histidine residue (His168). The substrate diffuses down the pore in the form of NH3, while the excess proton is cotransported through a highly conserved hydrogen-bonded His168-H1s318 pair. This constitutes a novel permeation mechanism that confers to the histidme dyad an essential mechanistic role that was so far unknown. [ABSTRACT FROM AUTHOR]

Voltage-gated K+ channels play central roles in human physiology, both in health and disease. A repertoire of inhibitors that are both potent and specific would therefore be of great value, not only as pharmacological agents but also as research tools. The small molecule RY785 has been described as particularly promising in this regard, as it selectively inhibits channels in the Kv2 subfamily with high potency. Kv2 channels are expressed in multiple cell types in humans, and are of particular importance for neuronal function. The mechanism of action of RY785 has not yet been determined at the molecular level, but functional studies indicate it differs from that of less specific inhibitors, such as quaternary-ammonium compounds or aminopyridines; RY785 is distinct also in that it is electroneutral. To examine this mechanism at the single-molecule level, we have carried out a series of all-atom molecular dynamics simulations based on the experimental structure of the Kv2.1 channel in the activated, open state. First, we report a 25-microsecond trajectory calculated in the absence of any inhibitor, under an applied voltage of 100 mV, which demonstrates outward K+ flow under simulation conditions at rates comparable to experimental measurements. Additional simulations in which either RY785 or tetraethylammonium (TEA) is introduced in solution show both inhibitors spontaneously enter the channel through the cytoplasmic gate, with distinct effects. In agreement with prior structural studies, we observe that TEA binds to a site adjacent to the selectivity filter, on the pore axis, thereby blocking the flow of K+ ions. RY785, by contrast, binds to the channel walls, off-axis, and allows K+ flow while the cytoplasmic gate remains open. The observed mode of RY785 binding, however, indicates that its mechanism of action is to stabilize and occlude a semi-open state of the gate, by bridging hydrophobic protein-protein interactions therein; this hypothesis would explain the puzzling experimental observation that RY785 recognition influences the gating currents generated by the voltage sensors, 3 nm away.

Long associated with cell death, hydrogen peroxide (H 2 O 2 ) is now known to perform many physiological roles. Unraveling its biological mechanisms of action requires atomic-level knowledge of its association with proteins and lipids, which we address here. High-level [MP2(full)/6-311++G(3df,3pd)] ab initio calculations reveal skew rotamers as the lowest-energy states of isolated H 2 O 2 (ϕ HOOH ∼ 112°) with minimum and maximum electrostatic potentials (kcal/mol) of -24.8 ( V s,min ) and 36.5 ( V s,max ), respectively. Transition-state, nonpolar trans rotamers (ϕ HOOH ∼ 180°) at 1.2 kcal/mol higher in energy are poorer H-bond acceptors ( V s,min = -16.6) than the skew rotamers, while highly polar cis rotamers (ϕ HOOH ∼ 0°) at 7.8 kcal/mol are much better H-bond donors ( V s,max = 52.7). Modeling H 2 O exhibit a similar range of stabilities ( 2 association with neutral and charged analogs of protein residues and lipid groups (e.g., ester, phosphate, choline) reveals that skew rotamers (ϕ HOOH = 84-122°) are favored in the neutral and cationic complexes, which display gas-phase interaction energies ( E CP , kcal/mol) of -1.5 to -18. The neutral and cationic complexes of H 2 O exhibit a similar range of stabilities ( E CP ∼ -1 to -18). However, considerably higher energies ( E O is a much poorer H-bond donor ( CP ∼ -14 to -36) are found for the H 2 O 2 complexes of the anionic ligands, which are stabilized by charge-assisted H-bond donation from cis and distorted cis rotamers (ϕ HOOH = 0-60°). H 2 O is a much poorer H-bond donor ( V s,max = 33.4) than cis -H 2 O 2 (Orabi, E. A.; English, A. M. E CP ∼ -11 to -20). Thus, by dictating the rotamer preference of H 2 O 2 , functional groups in biomolecules can discriminate between H 2 O 2 and H 2 O. Finally, exploiting the present ab initio data, we calibrated and validated our published molecular mechanics model for H 2 O 2 (Orabi, E. A.; English, A. M. J. Chem. Theory Comput . 2018 , 14 , 2808-2821) to provide an important tool for simulating H 2 O 2 in biology.

Polarizable potential models for the interaction of Li(+), Na(+), K(+), and NH4(+) ions with benzene are parametrized based on ab initio quantum mechanical calculations. The models reproduce the ab initio complexation energies and potential energy surfaces of the cation-π dimers. They also reproduce the cooperative behavior of "stacked", cation-π-π trimers and the anticooperative behavior of "sandwiched", π-cation-π trimers. The NH4(+) model is calibrated to reproduce the energy of the NH4(+)-H2O dimer and yields correct free energy of hydration and hydration structure without further adjustments. The models are used to investigate cation-π interactions in aqueous solution by calculating the potential of mean force between each of the four cations and a benzene molecule and by analyzing the organization of the solvent as a function of the cation-benzene separation. The results show that Li(+) and Na(+) ions are preferentially solvated by water and do not associate with benzene, while K(+) and NH4(+) ions bind benzene with 1.2 and 1.4 kcal/mol affinities, respectively. Molecular dynamics simulations of NH4(+) and of K(+) in presence of two benzene molecules in water show that cation-π and π-π affinities are mutually enhanced compared to the pairwise affinities, confirming that the cooperativity of cation-π and π-π interactions persists in aqueous solution.