Almost 50 years have passed from the first computer simulations of water, and a large number of molecular models have been proposed since then to elucidate the unique behavior of water across different phases. In this article, we review the recent progress in the development of analytical potential energy functions that aim at correctly representing many-body effects. Starting from the many-body expansion of the interaction energy, specific focus is on different classes of potential energy functions built upon a hierarchy of approximations and on their ability to accurately reproduce reference data obtained from state-of-the-art electronic structure calculations and experimental measurements. We show that most recent potential energy functions, which include explicit short-range representations of two-body and three-body effects along with a physically correct description of many-body effects at all distances, predict the properties of water from the gas to the condensed phase with unprecedented accuracy, thus opening the door to the long-sought “universal model” capable of describing the behavior of water under different conditions and in different environments.

Tinker-HP is massively parallel software dedicated to polarizable molecular dynamics.

Ten-eleven translocation (TET) enzymes catalyze stepwise oxidation of 5-methylcytosine (mC) to yield 5-hydroxymethylcytosine (hmC) and the rarer bases 5-formylcytosine (fC) and 5-carboxylcytosine (caC). Stepwise oxidation obscures how each individual base forms and functions in epigenetic regulation and prompts the question of whether TET enzymes primarily serve to generate hmC, or whether they are adapted to produce fC and caC as well. By mutating a single, conserved active site residue in human TET2, Thr1372, we uncovered enzyme variants that permit oxidation to hmC but largely eliminate fC/caC. Biochemical analyses, combined with molecular dynamics simulations, elucidated an active site scaffold that is required for WT stepwise oxidation and that, when perturbed, explains the mutants’ hmC-stalling phenotype. Our results suggest that the TET2 active site is shaped to enable higher-order oxidation and provide the first TET variants that could be used to probe the biological functions of hmC separately from fC and caC.