Interferon regulatory factor 1 (IRF-1) plays a vital role in cell proliferation and cell differentiation by acting as a tumor suppressor gene and its role is linked to various types of cancers, including leukemia and pre-leukemia myelodysplasia. Mutations in the coding region of the IRF-1 are likely to influence the IRF-1 and its DNA binding affinity. The molecular mechanism of the DNA recognition with the IRF-1 protein upon mutations is still unknown. In this study, we have elucidated the structural and functional behavior of the wild-type and mutant (K75E and E222K) IRF-1 proteins and their corresponding molecular mechanisms with DNA recognition at the molecular level, using molecular dynamics simulations. Furthermore, we also applied the docking approach to examine the binding between the IRF-1 protein and DNA upon mutations. This study evidently explains that, due to mutations, the IRF-1 structure loses its stability and becomes more flexible than the wild-type protein. This structural loss might affect IRF-1-DNA interaction and lead to the inhibition of cancer suppression. Identifying the effects of IRF-1 at the molecular level will be beneficial for designing drugs for IRF-1 associated cancers. These drugs should be designed so that they can help reactivate the IRF-1 function, by increasing the transcriptional activity, to treat leukemia. Communicated by Ramaswamy H. Sarma

FMS-like tyrosine kinase 3 (FLT3) gene mutations have been found in more than one-third of Acute Myeloid Leukemia (AML) cases. The most common point mutation in FLT3 occurs at the 835th residue (D835A/E/F/G/H/I/N/V/Y), in the activation loop region. The D835 residue is critical in maintaining FLT3 inactive conformation; these mutations might influence the interaction with clinically approved AML inhibitors used to treat the AML. The molecular mechanism of each of these mutations and their interactions with AML inhibitors at the atomic level is still unknown. In this manuscript, we have investigated the structural consequence of native and mutant FLT-3 proteins and their molecular mechanisms at the atomic level, using molecular dynamics simulations (MDS). In addition, we use the molecular docking method to investigate the binding pattern between the FLT-3 protein and AML inhibitors upon mutations. This study apparently elucidates that, due to mutations in the D835, the FLT-3 structure loses its conformation and becomes more flexible compared to the native FLT3 protein. These structural changes are suggested to contribute to the relapse and resistance responses to AML inhibitors. Identifying the effects of FLT3 at the molecular level will aid in developing a personalized therapeutic strategy for treating patients with FLT-3-associated AML.