If It’s Cryptic, How Do We Know It’s There?- Group 2

Although DHFR is traditionally considered a single-domain enzyme, evidence suggests that hydrogen bond networks may facilitate long-range communication between various parts of the enzyme. DHFR is a highly dynamic enzyme, and the hydrogen bonds within it are not static; they fluctuate as the enzyme undergoes conformational changes throughout its lifetime. Molecular dynamics simulations show that these hydrogen bonds form and break depending on the enzyme’s state.
Designing a cryptic site that communicates with the active site through temporal hydrogen bond pathways remains a significant challenge. Mutations in DHFR that lead to drug resistance often alter the enzyme’s hydrogen bond network. These mutations may weaken or eliminate specific hydrogen bonds that drugs rely on for strong binding, thereby reducing drug efficacy without significantly impacting substrate binding or catalysis.
The role of cryptic sites in facilitating drug binding must also be elucidated. Accordingly, the stability of hydrogen bond pathways will be investigated by binding drugs to cryptic sites identified as candidates.