Impact of lymphoma-linked Asn11Tyr point mutation on the interaction between Bcl-2 and a BH3 mimetic: Insights from molecular dynamics simulation.

Frequent mutations in the Bcl-2 anti-apoptotic protein are often implicated in diffuse large B-cell lymphoma (DLBCL), a disease profoundly resistant to drugs. Bcl-2-competitive inhibitors, "BH3 mimetics," activate apoptosis by interfering with the interactions between pro-apoptotic BH3 domains and the hydrophobic groove of Bcl-2. The aim of our research is to determine the potential of DLBCL-linked N11Y mutation to facilitate resistance against a "BH3 mimetic" using molecular dynamics simulation. Binding free energy calculations suggest a significant decrease in the binding affinity in the mutant model. In-depth analysis of the models using residue interaction network, dynamic cross-correlation, and free energy landscape approaches reveal that the mutation modifies the conformations of key residues, thereby altering the shape of the hydrophobic groove. This subsequently changes the ligand orientation and counteracts the phenomenon of LB region unwinding, a crucial event observed in the wild-type model. Lowest frequency motions captured by principal component analysis reflect the stretching of the groove for efficient ligand accommodation in the wild-type complex but not in the mutant model. This is the first in silico study that unravels the mechanism of drug resistance induced by a Bcl-2 mutation, which could be of great relevance while designing and tailoring therapeutics.