Neutron crystallography is an important complementary technique to X-ray crystallography since it provides details of the hydrogen (H) atom and proton (H + ) positions in biological molecules. Furthermore, as neutrons (of the energies used for crystallographic experiments) are a non-destructive probe, the resulting structures are free from radiation damage even at room temperature (Blakeley et al., 2015). Knowledge of H-bonding networks, water molecule orientations and protonation states, along with details of hydrophobic and electrostatic interactions, can prove vital towards a better understanding of many biological processes, such as enzyme mechanisms (Casadei et al., 2014;Vandavasi et al., 2016) and ligand binding (Howard et al., 2016), and can help guide structure-based drug design (Huang et al., 2014).The first neutron crystallography study of a clinically used drug bound to its target was that of acetazolamide (AZM), a sulfonamide, which binds with high affinity to human carbonic anhydrase isoform II (Fisher et al., 2012). Human carbonic anhydrases (hCA) are zinc metalloenzymes that catalyze the interconversion of CO 2 and H 2 O to HCO 3 À and H + , an important reaction for many physiological processes including respiration, fluid secretion and pH regulation. As such, hCA isoforms are prominent clinical targets for treating various diseases, such as glaucoma and epilepsy. hCA II is one of 12 catalytically active isoforms and, due to sequence conservation between them, substantial offtarget binding to other isoforms occurs, reducing drug efficiency and causing side effects. Hence, there is a need to design effective hCA isoform-specific drugs. Over 400 X-ray crystal structures have been determined for hCA II, with around half of these in complex with inhibitors, yet despite the large amount of structural data available, key details regarding the H-atom positions of the protein and solvent and the charged state of the bound inhibitor were missing. The room-temperature neutron structure of hCA II in complex with AZM at 2.0 Å resolution revealed that the charged state of bound AZM was the anionic form, along with details of hydration, H bonding and hydrophobic interactions between AZM and hCA II (Fisher et al., 2012).In this issue of IUCrJ, McKenna and co-workers (Aggarwal et al., 2016) describe X-ray and neutron crystallography studies of hCA II in complex with a second sulfonamide inhibitor, methazolamide (MZM) -a methyl derivative of AZM that is preferred clinically for reasons such as greater stability, longer half life, lower dose and fewer side effects. They report the room-temperature neutron structure of hCA II in complex with MZM at 2.2 Å resolution, revealing the inhibitor is also bound in the anionic form, along with details of hydration, H bonding and hydrophobic interactions between MZM and hCA II. They then compare the binding of the two inhibitors in the room-temperature neutron structures, and in particular show that more water molecules are displaced from the active site by MZM than AZM, rel...