… fails, such as the design of large, asymmetric interfaces … A key challenge in designing hydrogen
bond networks is … in which every buried polar group has a hydrogen bond partner. HBNet …

… interface, which highlights two design lessons (fig. S12): (i) the importance of intermolecular
… attempts to design buried hydrogen bonds across interfaces have routinely failed (43). Polar …

… These results highlight the importance of hydrogen bonds … of buried non-polar atoms in V L
–V H interfaces compared with … hydrogen bonds in computational design is still challenging, …

… In this essay, I consider how the successes and failures in this new … These designs also
highlight the control afforded by … For example, the buried central hydrogen bond networks that …

… and buried polar interaction networks, which have remained … in ideal folds form hydrogen
bonds that stabilize secondary … to other parts of the Fv, highlighting its structural modularity. We …

… Designing novel PPIs poses a fundamental challenge to our … highlight successful design
cases and discuss challenges in … buried hydrogen bonds account for most of the failure in de …

… and hydrogen bonding between the buried hydrogen-bond … A challenge when designing
polar interactions is to ensure … The most frequent reasons for failure are insolubility and the …

… the number of buried unsatisfied hydrogen bonding groups. … of the successful ProteinMPNN
designs, using color to highlight … to discriminate successful from unsuccessful designs, we …

… are shown, with red error bars indicating uncertainty) and … optimization for designing
buried hydrogen bond networks — … protein design can be applied to, we highlight a subset of …

… highlight particular choices made in our design protocol, such as the number of hydrogen
bonds… to understand how designs managed to bury polar atoms at their interfaces. The fraction …