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Water molecules play a key role in all biochemical processes. They help define the shape of proteins, and they are reactant or product in many reactions and are released as ligands are bound. They facilitate the transfer of protons through transmembrane proton channel, pump and transporter proteins. Continuum electrostatics (CE) force fields used by program Multiconformation CE (MCCE) capture electrostatic interactions in biomolecules with an implicit solvent, which captures the averaged solvent water equilibrium properties. Hybrid CE methods can use explicit water molecules within the protein surrounded by implicit solvent. These hybrid methods permit the study of explicit hydrogen bond networks within the protein and allow analysis of processes such as proton transfer reactions. Yet hybrid CE methods have not been rigorously tested. Here, we present an explicit treatment of water molecules in the Gramicidin A (gA) channel using MCCE and compare the resulting distributions of water molecules and key hydration features against those obtained with explicit solvent Molecular Dynamics (MD) simulations with the nonpolarizable CHARMM36 and polarizable Drude force fields. CHARMM36 leads to an aligned water wire in the channel characterized by a large absolute net water dipole moment; the MCCE and Drude analysis lead to a small net dipole moment as the water molecules change orientation within the channel. The correct orientation is not as yet known, so these calculations identify an open question. • Water is the primary cellular solvent, yet is challenging to simulate computationally. Here we simulate water molecules in the Gramicidin A channel comparing Monte Carlo (MC) sampling with a continuum electrostatics and Molecular Dynamics (MD) calculations with the non-polarizable CHARMM36 and polarizable Drude force fields. • These give different water properties, with classical MD yielding well oriented water wires, while the Drude or continuum electrostatics force fields lead to more disordered water molecules, often changing orientation in the middle of the channel. [ABSTRACT FROM AUTHOR]

The oxidation of water to O2 is catalyzed by the Oxygen Evolving Complex (OEC), a Mn4CaO5 complex in Photosystem II (PSII). The OEC is sequentially oxidized from state S0 to S4. The S2 state, (MnIII)(MnIV)3, coexists in two redox isomers: S2,g=2, where Mn4 is MnIV and S2,g=4.1, where Mn1 is MnIV. Mn4 has two terminal water ligands, whose proton affinity is affected by the Mn oxidation state. The relative energy of the two S2 redox isomers and the protonation state of the terminal water ligands are analyzed using classical multi-conformer continuum electrostatics (MCCE). The Monte Carlo simulations are done on QM/MM optimized S1 and S2 structures docked back into the complete PSII, keeping the protonation state of the protein at equilibrium with the OEC redox and protonation states. Wild-type PSII, chloride-depleted PSII, PSII in the presence of oxidized YZ/protonated D1-H190, and the PSII mutants D2-K317A, D1-D61A, and D1-S169A are studied at pH 6. The wild-type PSII at pH 8 is also described. In qualitative agreement with experiment, in wild-type PSII, the S2,g=2 redox isomer is the lower energy state; while chloride depletion or pH 8 stabilizes the S2,g=4.1 state and the mutants D2-K317A, D1-D61A, and D1-S169A favor the S2,g=2 state. The protonation states of D1-E329, D1-E65, D1-H337, D1-D61, and the terminal waters on Mn4 (W1 and W2) are affected by the OEC oxidation state. The terminal W2 on Mn4 is a mixture of water and hydroxyl in the S2,g=2 state, indicating the two water protonation states have similar energy, while it remains neutral in the S1 and S2,g=4.1 states. In wild-type PSII, advancement to S2 leads to negligible proton loss and so there is an accumulation of positive charge. In the analyzed mutations and Cl− depleted PSII, additional deprotonation is found upon formation of S2 state. [ABSTRACT FROM AUTHOR]

The gating properties of the inositol 1, 4, 5-trisphosphate (IP 3 ) receptor (IP 3 R) are determined by the binding and unbinding capability of Ca 2+ ions and IP 3 messengers. With the patch clamp experiments, the stationary properties have been discussed for Xenopus oocyte type-1 IP 3 R (Oo-IP 3 R1), type-3 IP 3 R (Oo-IP 3 R3) and Spodoptera frugiperda IP 3 R (Sf-IP 3 R). In this paper, in order to provide insights about the relation between the observed gating characteristics and the gating parameters in different IP 3 Rs, we apply the immune algorithm to fit the parameters of a modified DeYoung-Keizer model. By comparing the fitting parameter distributions of three IP 3 Rs, we suggest that the three types of IP 3 Rs have the similar open sensitivity in responding to IP 3 . The Oo-IP 3 R3 channel is easy to open in responding to low Ca 2+ concentration, while Sf-IP 3 R channel is easily inhibited in responding to high Ca 2+ concentration. We also show that the IP 3 binding rate is not a sensitive parameter for stationary gating dynamics for three IP 3 Rs, but the inhibitory Ca 2+ binding/unbinding rates are sensitive parameters for gating dynamics for both Oo-IP 3 R1 and Oo-IP 3 R3 channels. Such differences may be important in generating the spatially and temporally complex Ca 2+ oscillations in cells. Our study also demonstrates that the immune algorithm can be applied for model parameter searching in biological systems.