Anchor points identification. The first step of the protocol is the identification of the locations for the initial placement of water molecules (Fig. ). For that, hydrogen bond anchors points (AP) are defined on the target surface, using opportune SMARTS patterns (File S1). Two different methods have been tested for the selection of AP: one more strict including only standard HB acceptors and donors (AP polar ), and another more permissive which includes also non-polar hydrogens (AP all ). For each AP, hydrogen bond anchor vectors (AV) with a length of 2.8 Å are generated on the heavy atom, with number and angles varying according to its valence and hybridization. Initially, the pool of APs contains only the anchor points on the dry target which are used for the placement of the first hydration layer. Then, each newly added water will add its APs, which will be used to build subsequent layers.