Differential Binding Affinities of Anti-Apoptotic MCL-1 and A1 Proteins for the Pro-Apoptotic BH3 Peptides: Understanding the Molecular Basis using MD Simulations

Abstract

The Bcl-2 family of proteins plays a crucial role in the regulation of Apoptosis through heterodimerization between pro- (e.g. Bim, Puma, Bad) and anti-apoptotic (e.g. Bcl-XL, MCL-1, A1) members. The anti-apoptotic proteins however display different binding specificities and affinities towards the BH3 peptides of pro-apoptotic partners. The current study investigates the differences in binding affinities of peptides derived from pro-apoptotic proteins towards MCL-1 and A1 using MD simulations. Simulations each for a period of 100 ns has been carried out for MCL-1/A1 proteins in complex with Puma and Bad BH3 peptides. Stability of non-covalent interactions between the peptides and the protein was analyzed. The MCL-1-Puma complex simulation reveals the presence of very strong interactions between the acidic residues at the N-terminus of Puma with the basic residues present in helix H3 of protein. Moreover, the helix H4 & H6 exhibit very stable hydrophobic contacts with the C-terminal residues of Puma. The equivalent interactions are absent in A1: Puma complex simulation but it reveals the presence of a strong hydrophilic contact involving the ARG from “LR” motif of the peptide. These observations collectively may account for the slightly higher binding affinity of Puma towards MCL-1. In the simulation of the modeled MCL-1-Bad complex, interestingly we did not observe any stable interactions including those involving the ARG of the ‘LR motif’ with the protein. Involvement of “LR” motif in peptide-protein interactions was previously hypothesized to be important in high binding affinity of Bad towards Bcl-XL [1]. The negligible affinity of Bad towards MCL-1 can be attributed to these factors. [1] Lama and Sankararamakrishnan, Proteins73, 492-514 (2008)