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Abstract Liquid water can be supercooled up to about 50~K below the melting point before undergoing homogeneous ice nucleation. Based on experimental thermodynamic observations and computer simulations it was hypothesized that below this temperature and at pressures of several kbar water undergoes a liquid-liquid phase transition (LLPT) and the transition line ends at a second critical point. However, challenges in experiments and simulations at such deep cooling leave doubts about the nature of the LLPT and the existence of the critical point.Here we use molecular dynamics simulations with a highly accurate and computationally efficient polarizable water model to establish the character of the LLPT and identify the location of the second critical point. Our microsecond-long simulations provide the first direct evidence of a well-defined moving interface between low-density and high-density water at conditions near the phase boundary. This is the ultimate proof of a first-order transition between two liquid phases with distinct free energy basins separated by a barrier, resolving a long-standing debate. These results provide new perspectives on supercooled water under pressure simulated with an accurate and realistic model suitable for studies of water in confined geological and biological environments. 

The oscillator of the cyanobacterial circadian clock relies on the ability of the KaiB protein to switch reversibly between a stable ground-state fold (gsKaiB) and an unstable fold-switched fold (fsKaiB). Rare fold-switching events by KaiB provide a critical delay in the negative feedback loop of this posttranslational oscillator. In this study, we experimentally and computationally investigate the temperature dependence of fold switching and its mechanism. We demonstrate that the stability of gsKaiB increases with temperature compared to fsKaiB and that the Q10 value for the gsKaiB → fsKaiB transition is nearly three times smaller than that for the reverse transition in a construct optimized for NMR studies. Simulations and native-state hydrogen-deuterium exchange NMR experiments suggest that fold switching can involve both partially and completely unfolded intermediates. The simulations predict that the transition state for fold switching coincides with isomerization of conserved prolines in the most rapidly exchanging region, and we confirm experimentally that proline isomerization is a rate-limiting step for fold switching. We explore the implications of our results for temperature compensation, a hallmark of circadian clocks, through a kinetic model. 

Abstract The restrained electrostatic potential (RESP) approach is a highly regarded and widely used method of assigning partial charges to molecules for simulations. RESP uses a quantum-mechanical method that yields fortuitous overpolarization and thereby accounts only approximately for self-polarization of molecules in the condensed phase. Here we present RESP2, a next generation of this approach, where the polarity of the charges is tuned by a parameter, δ, which scales the contributions from gas- and aqueous-phase calculations. When the complete non-bonded force field model, including Lennard-Jones parameters, is optimized to liquid properties, improved accuracy is achieved, even with this reduced set of five Lennard-Jones types. We argue that RESP2 with δ  ≈ 0.6 (60% aqueous, 40% gas-phase charges) is an accurate and robust method of generating partial charges, and that a small set of Lennard-Jones types is a good starting point for a systematic re-optimization of this important non-bonded term.