They showed which the S4 helix, with four arginines, inserts into the microsomal membrane with an apparent free energy of +0

They showed which the S4 helix, with four arginines, inserts into the microsomal membrane with an apparent free energy of +0.5 kcal/mol. underestimate the ability of the bilayer to adapt to charged and polar groups. This is an active area of research, and there is no doubt that a consensus view of arginine in membranes will soon emerge. Keywords:Biophysics, Biophysics of ion channels, Structure, Arginine, Bilayer, Hydrophobicity == Introduction == Arginine is usually often considered to be the most hydrophilic of the 20 natural amino acids. Its side chain contains a large guanidinium moiety that has the capacity for up to six hydrogen bonds (Fig. 1). The resonance-stabilized side chain has a pKa over 12, and thus, arginine is usually protonated, and positively charged, in essentially all biological environments. However, despite its charged and polar nature, arginine frequently plays a critical functional role within membranes. Membrane-inserted arginines are found in ion channels and other membrane proteins as well as in pore-forming, antimicrobial and cell-penetrating peptides. The function of arginine in membrane proteins and even its presence within the hydrocarbon core of the membrane pose many unanswered questions. In this review we summarize the recent literature and discuss a recent controversy about arginine in membranes. == Fig. 1. == Physical chemistry of arginine. The side chain of arginine is composed of a hydrophobic propyl moiety and a large, polar, cationic guanidinium group. The resonance-stabilized guanidinium, with a pKa around 1213, is usually protonated and cationic under almost all conditions. Nine different atoms in the side chain have significant partial charges, shown on theright. The guanidinium group contains five dipolar NH protons capable of donating hydrogen bonds and one pair of electrons capable of taking a hydrogen bond. In terms of the potential for interacting with lipid polar groups, it should be noted that hydrogen bond donor moieties are rare in membranes: Phospholipids provide mostly hydrogen bond acceptor groups, in the form of ester bonds and phosphate oxygens The arginine controversy is derived from significant discrepancies between experimental and computational studies concerning the energetics of arginine insertion into the bilayer hydrocarbon core. The issues arise because arginine is very hydrophilic and the hydrocarbon core of an unperturbed lipid bilayer membrane is one of the most hydrophobic microenvironments found in nature, with physicalchemical properties that are very similar to a liquid alkane phase (White and Wimley 1999;White et al. 2001). The hydrocarbon core is believed to Didanosine impart a strict barrier to the permeation of polar or charged solutes through the bilayer. However, the bilayer’s hydrocarbon core is positioned between the two chemically heterogeneous interfacial zones, which are composed of some hydrocarbon but mainly lipid polar groups and water. The bilayer interfacial zones thus have many hydrogen-bonding groups that can interact with a membrane-inserted arginine. In this review we propose that these interactions and the ability of the bilayer to deform make it possible for arginine to insert into bilayers, especially when it is surrounded by hydrophobic residues. == Arginine Becomes Controversial: The Potassium Channel, KvAP == Perhaps the biggest controversy in membrane biophysics in the first decade of the twenty-first century was associated with the structure and function of the voltage-gated potassium channel KvAP (Fig. 2). Voltage-sensitive ion channels control the potassium flow across membranes down the electrochemical gradient and are critical for the propagation of electrical signals in the nervous system. These channels open and close in response to the transmembrane electrochemical potential in Didanosine a process that involves the motion of the so-called voltage sensor domain name. The voltage sensor domain name of a classical voltage-gated potassium channel is composed of four hydrophobic segments. One of them (S4) contains at least four arginines, and this arginine-rich helix responds to changes in transmembrane voltage by altering its disposition in the bilayer, thereby opening and closing the channel. In 2003 MacKinnon and colleagues reported, for the first time, the structure of a full-length voltage-gated potassium channel, KvAP, which contradicted previous models of the channel and positioned the four arginines of the S4 segment in direct contact with the hydrocarbon tails of lipids (Jiang et al. 2003a,2003b). Furthermore, they proposed that this S4 helix moves like a lever arm or a paddle, covering a distance of about 20 across the membrane during channel opening and closing. Importantly, these views Rabbit Polyclonal to POLE1 were based not only around the crystal structure, which was distorted due to the presence of an antibody (which enabled crystallization) attached in close proximity to the S4 helix, but also on electrophysiological assays used to investigate the movement of the voltage sensor upon channel opening and closing (Jiang et al. 2003a,b). == Fig. 2. == Structure of the full-length KvAP potassium channel. This membrane-spanning protein has a tetrameric structure with a central channel domain name and four voltage sensor domains around Didanosine the periphery. The.