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KEY WORDS: lipid-protein interactions, peptide-bilayer interactions, membrane-active peptides, antimicrobial peptides, thermodynamics, bilayer structure, soluble protein folding
ABSTRACT
Stably folded membrane proteins reside in a free energy minimum determined by the interactions of the peptide chains with each other, the lipid bilayer hydrocarbon core, the bilayer interface, and with water. The prediction of three-dimensional structure from sequence requires a detailed understanding of these interactions. Progress toward this objective is summarized in this review by means of a thermodynamic framework for describing membrane protein folding and stability. The framework includes a coherent thermodynamic formalism for determining and describing the energetics of peptide-bilayer interactions and a review of the properties of the environment of membrane proteins-the bilayer milieu. Using a four-step thermodynamic cycle as a guide, advances in three main aspects of membrane protein folding energetics are discussed: protein binding and folding in bilayer interfaces, transmembrane helix insertion, and helix-helix interactions. The concepts of membrane protein stability that emerge provide insights to fundamental issues of protein folding.
PERSPECTIVES AND OVERVIEW
Introduction
Only two structural motifs (Figure 1) have been observed for membrane proteins (MPs): membrane-spanning alpha-helix bundles and beta-barrels, the former being predominant. Analyses of the complete genomic sequences for several organisms indicate that 20-30% of all open reading frames code for the helixbundle motif (4,157). A frequently observed submotif is interfacial helices connected to adjacent transmembrane (TM) helices, illustrated by the fd coat protein. As shown schematically in Figure 1, the secondary structure elements of MPs are in contact with each other, the bilayer HC core, the bilayer interface, and, of course, water. The prediction of MP structure and stability requires that the energetics of the interactions of the peptide chains with each other and with the various components of their environment be understood.
We present a comprehensive summary of our current understanding of these energetics using a coherent thermodynamic approach that may help set some directions for further progress. The presentation is organized around several guiding questions: What are the general features of MPs? How are they assembled? How can their thermodynamic stability be described? What is the nature of the lipid bilayer as a host phase for MPs? What are the dominant forces that determine structure and stability? What can the folding and...