Determinants of Substrate Specificity in APOBEC3B

APOBEC3B (A3B) is a newly discovered driver of mutation in many cancers. We use computational tools to revert a recent crystal structure of an A3B construct to its native sequence, and run molecular dynamics simulations to study its underlying dynamics and substrate recognition mechanisms. The A3B-oligonucleotide substrate simulations show a series of dynamic substrate-protein contacts that correlate with previous work on A3B substrate selectivity. A second series of simulations in which the target cytosine nucleotide was computationally mutated from a deoxyribose to a ribose showed a change in sugar ring pucker, leading to a rearrangement of the binding site and revealing a potential intermediate in the binding pathway. Finally, apo simulations of A3B beginning in the open state experience a rapid and consistent closure of the binding site, reaching a conformation incompatible with substrate binding. These simulations agree with previous experimental studies, and we report the atomistic details of these events to further therapeutic studies on A3B.