Protein surface chemistry encodes an adaptive tolerance to desiccation.

Cellular desiccation-the loss of nearly all water from the cell-is a recurring stress that drives widespread protein dysfunction. To survive, part of the proteome must resume function upon rehydration. Which proteins tolerate desiccation, and the molecular determinants that underlie this tolerance, are largely unknown. Here, we use quantitative mass spectrometry and structural proteomics to show that certain proteins possess an innate capacity to tolerate extreme water loss. Structural analyses point to protein surface chemistry as a key determinant of desiccation tolerance, which we test by showing that rational surface mutants can convert a desiccation-sensitive protein into a tolerant one. We also find that highly tolerant proteins are responsible for the production of small-molecule building blocks, while intolerant proteins are involved in energy-consuming processes such as ribosome biogenesis. We propose that this functional bias enables cells to kickstart their metabolism and promote cell survival following desiccation and rehydration. A record of this paper's transparent peer review process is included in the supplemental information.