Understanding Periperal Membrane Protein Interactions | BPS Thematic Meeting

Understanding Peripheral Membrane Protein Interactions: Structure, Dynamics, Function and Therapy

Poster Abstracts

13-POS Board 13 REHT-PMP: AN EFFICIENT SAMPLING METHOD FOR CAPTURING THE CONFORMATIONAL CHANGES OF PERIPHERAL MEMBRANE PROTEINS ON LIPID BILAYERS Chandramouli Natarajan 1 ; Anand Srivastava 1 ; 1 Indian Institute of Science, Molecular Biophysics Unit, Bangalore, India Accurately sampling the membrane-bound conformations of peripheral membrane proteins (PMP) using classical all-atom molecular dynamics simulations (AAMD) is a formidable enterprise due to the wide rugged free energy landscape of the protein-membrane system. In this work, we first showcase the utility of replica exchange with hybrid tempering (REHT) method in capturing the membrane-bound conformations of PMPs by testing it on the Osh4 amphipathic lipid-packing sensor (ALPS) motif, a 27 amino-acid membrane-binding peptide. We show that REHT-PMP samples all the membrane-bound conformations of the Osh4 ALPS peptide observed in extensive AAMD simulations and does it highly efficiently. We clearly show that the peptide prefers horizontal conformations over vertical ones. However, the transition between the two configurations is not uncommon, as our calculations reveal a ∼ 1 kT free energy difference between the two conformations. Interestingly, our simulations also show that the transition from vertical to horizontal conformation involves limited unfolding of the main helix’s last turn, an essential feature required for the transition. Further, to show the ability of REHT PMP not just to capture such small conformational changes but also to accelerate extensive folding processes upon membrane binding, we took the N-terminal region of alpha-synuclein ( α S). This intrinsically disordered protein adopts an alpha-helix upon binding to anionic membranes. We successfully sampled the folding pathway of two wild-type constructs of α S: the first 30 and 50 N-terminal residues, named α S30 and α S50, respectively, on three different anionic membranes. Finally, we show the lack of proper folding of α S50, upon A30P mutation, a familial Parkinsonian mutant. From our findings, we conclude that REHT-PMP efficiently samples the membrane-bound conformations and conformational changes of small PMPs and provides additional insights that are often unavailable with classical AAMD simulations.

47