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Feeling the Hidden Mechanical Forces in Lipid Bilayer Is an Original Sense Andriy Anishkina, Stephen H

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Feeling the Hidden Mechanical Forces in Lipid Bilayer Is an Original Sense Andriy Anishkina, Stephen H PERSPECTIVE Feeling the hidden mechanical forces in lipid bilayer is an original sense Andriy Anishkina, Stephen H. Loukinb, Jinfeng Tengb, and Ching Kungb,c,1 aDepartment of Biochemistry and Center for Computational Proteomics at the Huck Institute of Life Sciences, Pennsylvania State University, University Park, PA 16802; and bLaboratory of Molecular Biology and cDepartment of Genetics, University of Wisconsin–Madison, Madison, WI 53706 Edited by Roderick MacKinnon, The Rockefeller University and Howard Hughes Medical Institute, New York, NY, and approved April 15, 2014 (received for review January 21, 2014) Life’s origin entails enclosing a compartment to hoard material, energy, and information.The envelope necessarily comprises amphipaths, such as prebiotic fatty acids, to partition the two aqueous domains. The self-assembled lipid bilayer comes with a set of properties including its strong anisotropic internal forces that are chemically or physically malleable. Added bilayer stretch can alter force vectors on embedded proteins to effect conformational change. The force-from-lipid principle was demonstrated 25 y ago when stretches opened purified Escherichia coli MscL channels reconstituted into artificial bilayers. This reductionistic exercise has rigorously been recapitulated recently with two + vertebrate mechanosensitive K channels (TREK1 and TRAAK). Membrane stretches have also been known to activate various voltage-, ligand-, + or Ca2 -gated channels. Careful analyses showed that Kv, the canonical voltage-gated channel, is in fact exquisitely sensitive even to very small tension. In an unexpected context, the canonical transient-receptor-potential channels in the Drosophila eye, long presumed to open by ligand binding, is apparently opened by membrane force due to PIP2 hydrolysis-induced changes in bilayer strain. Being the intimate medium, lipids govern membrane proteins by physics as well as chemistry.This principle should not be a surprise because it parallels water’s paramount role in the structure and function of soluble proteins. Today, overt or covert mechanical forces govern cell biological processes and produce sensations. At the genesis, a bilayer’s response to osmotic force is likely among the first senses to deal with the capricious primordial sea. mechanosensitivity | force sensing | channel gating | bilayer mechanics | touch To compete successfully, organisms must α-helixcantiltit.Aforcecanalsostrainthe multiple short- and long-distance forces evolve effective reactions to earth’s physical bond and displace the partners, like stretch- among atoms and feeding them into New- stimuli: heat, force, voltage, and chemical ing or bending the helix. The bond breaks tonian laws of motion is the basis of mo- ligands. Emil Fischer’s lock-and-key binding when work (force times displacement) lecular dynamics simulation (MDS), which between molecules is well known and exceeds the bond energy. For example, it in recent decades has successfully analyzed − explains such overt senses as vision, smell, takes ∼4pN(4× 10 12 N) to break a hy- and explained the many workings of mac- and most tastes. We also understand voltage drogen bond, ∼1,600 pN to break a C–C romolecules and their assembly (4, 5). Some sensing. For example, a charge-bearing helix covalent bond (Fig. S1). Ligand–protein or forces relevant to biology and used in MDS traversing the electric field across the lipid protein–protein binding also mechanically are listed in Fig. S1. Some findings might bilayer can mechanically drive conforma- strains the bonds between protein do- surprise us. For example, most of the time tional changes of embedded ion channels mains to effect long-range conformational in catalysis is spent on the diffusion to and or enzymes (1). Heat and force are universal, changes. The last 100 y of mechanochem- from the catalytic site, mechanically posi- governing all matters and reactions. A chal- istry have shown how mechanical forces tioning the substrates and products; whereas lenge to current biology is to understand govern even inorganic chemical reactions the very stage of chemical transformation, of how Nature chooses and uses her molecular (2). Many steps in biochemical reactions or which we tend to fixate, happens almost thermometers and force gauges. We review other molecular processes can therefore be instantaneously. the basis of force sensing, emphasizing the simulated by explicitly stating the New- roles of the lipid bilayer mechanics. tonian forces involved and following the The Mechanics of the Lipid Bilayer motions of the components—an approach A surface tension appears at any liquid–liquid Biological Mechanisms Are Ultimately bringing invaluable insights into molecular or liquid–gas interface. Recall that at a Mechanics underpinnings of life. The 2013 Chemistry hexane–water interface, the surface tension Textbooks describe the energy minimum Nobel was awarded for the development appears because water molecules there are when atoms are brought to an equilibrium of molecular dynamics and quantum me- deprived of half of their hydrogen-bonding distance (bond length), at which, there is zero chanical approaches to simulate complex partners they enjoy in the bulk. Thermal force between them because their mutual chemical systems. How the paired atoms attraction balances repulsion. Thermal oscil- move upon a perturbation can be described Author contributions: A.A., S.H.L., J.T., and C.K. wrote the paper. lations or external forces change the bond by a set of laws and numerical parame- The authors declare no conflict of interest. “ ” length and generate compressive or expan- ters called the force field (3). In macro- This article is a PNAS Direct Submission. sive forces in the bond, much like with molecules, long-distance Lennard-Jones 1To whom correspondence should be addressed. E-mail: ckung@ a spring. External force acting on an atom and electrostatic forces come into play wisc.edu. can simply move the whole bonded assem- during conformational change. Reposition- This article contains supporting information online at www.pnas.org/ bly. For example, pulling one end of an ing atoms by iteratively calculating the lookup/suppl/doi:10.1073/pnas.1313364111/-/DCSupplemental. 7898–7905 | PNAS | June 3, 2014 | vol. 111 | no. 22 www.pnas.org/cgi/doi/10.1073/pnas.1313364111 Downloaded by guest on October 1, 2021 dispersion of the surface also makes mole- to take a better-matched conformation. positive curvature. Asymmetric insertions PERSPECTIVE cules less densely packed in the few inter- Reducing the acyl chain length from PC20 to of exogenous amphipaths activate these facial layers, thus decreasing the repulsion PC18 converts the reconstituted gramicidin channels (14), consistent with the bilayer- between the neighbors (6). Qualitatively A from a stretch-activated to a stretch- coupling hypothesis (26). The lipid force similar interfacial forces develop in the inactivated channel (12). Besides thinning, a profile and how stretch relates to MscL lipid bilayer. However, there are critical stretch can also change the magnitude and gating has been examined by MDS (10). In distinctions. Molecules at a liquid interface direction of the force vectors on the protein. line with the role of the bilayer’s focused are not restrained from freely joining the Chemically changing bilayer composition by lateral tension (Fig. 1B), random and scan- bulk. Water in a sea of hexane will shrink inserting impurities or through lipid me- ning mutagenesis showed that replacing hy- into a sphere. Adding more water increases tabolism can have the same effect (Fig. 1B). drophobic with hydrophilic residues in M1 the sphere’s volume but reduces the relative Although these principles are general, we or M2 at the outer rim of MscL removes number of water at the surface, with no chose to discuss ion channels among mem- mechanosensitivity in vitro and in vivo (27). change in surface tension. In contrast, the braneproteinsbecausetheiractivitiescan The miniprotein antibiotic gramicidin A polar lipid head is stuck with its nonpolar be examined easily and quantitatively, even from Bacillus brevis readily forms cation tail making the bilayer a “surface without at the level of single proteins and down channels in bilayers by pair-wise stacking. It bulk.” Typical membrane lipids tend to to a microsecond time resolution (13) by has been used to examine the role of vari- compact into a bilayer sheet instead of electric means. ous chemical and physical properties of a droplet. Adding lipids enlarges the sheet the bilayer in quantitative details (28). Over but does not change the exposed-to-hidden The Force-from-Lipid Principle the years, the force-from-lipid principle has surface ratio per molecule. Water molecules The force-from-lipid principle was estab- gradually been used to understand eukary- strongly bond with the polar atoms of the lished some 25 y ago from the study of the otic processes as well. More recently, this head groups or the glycerol, although bar- mechanosensitive channels from Escherichia principle has been rigorously extended to red from the nonpolar hydrocarbon tails. coli (14, 15). Their discovery, atomic struc- animal ion channels as summarized below. tures, and biological roles have been peri- Thus, a sharp lateral tension develops at the + level of the lipid neck. As a self-assembled odically reviewed (see refs. 16 and 17 and Mechanosensitive Two-Pore-Domain K citations therein). Briefly, the key observa- Channels entity at equilibrium, this tension
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