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Proteins that are functional at ambient conditions do not necessarily work at extreme conditions of temperature T and pressure P. Furthermore, there are limits of T and P above which no protein has a stable functional state. Here, we show that these limits and the selection mechanisms for working proteins depend on how the properties of the surrounding water change with T and P. We find that proteins selected at high T are superstable and are characterized by a nonextreme segregation of a hydrophilic surface and a hydrophobic core. Surprisingly, a larger segregation reduces the stability range in T and P. Our computer simulations, based on a new protein design protocol, explain the hydropathy profile of proteins as a consequence of a selection process influenced by water. Our results, potentially useful for engineering proteins and drugs working far from ambient conditions, offer an alternative rationale to the evolutionary action exerted by the environment in extreme conditions. DOI:https://doi.org/10.1103/PhysRevX.7.021047 Published by the American Physical Society under the terms of the Creative Commons Attribution 4.0 International license. Further distribution of this work must maintain attribution to the author(s) and the published article’s title, journal citation, and DOI. Published by the American Physical Society