Abstract
We have analyzed the dynamics of three different peptides bound to HLA-B*57:01 with and without abacavir, an antiretroviral drug used mainly to treat acquired immune deficiency syndrome (AIDS) caused by human immunodeficiency virus (HIV) type 1. Abacavir is associated with drug hypersensitivity reactions in 2% to 8% of treated patients. This hypersensitivity is strongly associated with human leukocyte antigen (HLA)-B*57:01 positive patients, but not patients carrying closely related alleles HLA-B*57:03, HLA-B*57:02 and HLA-B*58:01. Using molecular dynamics (MD) we found that abacavir alters the conformations adopted by peptides bound to HLA-B*57:01, as well as reducing their flexibility. The presence of abacavir has a direct impact on the dynamics and the conformational space available to peptides bound to HLA-B*57:01, likely influencing abacavir-induced immune self-reactivity. Abacavir binds dynamically, forming variable interactions with HLA-B*57:01 that are not accessible from static crystallographic snapshots, and may explain its specificity to HLA-B*57:01. The main contribution of abacavir to complex stability is through its effect on the shape of the binding groove, rather than through direct interactions with binding pockets. Understanding how dynamics influences the interactions of abacavir with HLA-B*57:01 and bound peptides will be important for developing safer antiretroviral drugs for the treatment and prevention of HIV.