Wednesday, January 2, 2013

Ion channel selectivity to ions with selectivity filters and other structures


Ion channels like proton (H+), sodium, potassium, calcium and chlorine channels let ions through cell membranes selectively by having narrow point in the tunnel that can only let through ions (or ion-water complexes) of certain size and charge. Charge selectivity depends on electrostatic attraction or repulsion depending on which amino acids are inside ion channel. Much of ion channel proteins is made of helical amino acid chains (alpha-helix) and these have tendency to align positive and negative charges consistently through helix (negative parts aimed at one side of cell membrane and positive parts to other parts).
Chart of amino acids. Pink areas are parts that connect amino acids together in proteins/peptides and other parts determine which charge amino acid has in proteins. "Polar basic" amino acids usually have positive charge while "polar acidic" amino acids have negative charge but collisions with reactive elements can have less predictable effect on charges.  


Voltage sensitivity can be achieved with positively charged amino acids through membranes. Above illustration is about sodium channel but many ion channels have similar 4 repeating groups. Those 4 repeating groups form 1 pore through cell membrane that is about 0,3-0,5 nanometers wide (radius of sodium is about 0,18 nm). 4th helix in all of these groups detect membrane voltage by being attracted to more negative side of membrane and with its pull it closes or opens depending on direction of charges. During resting phase cell is more negative inside and during electric impulse inside becomes more positive than outside. Larger voltage difference pulls-pushes charged parts with greater mechanical force. Other voltage gated ion channels have likely similar mechanisms involved but in others both charges could be in use as voltage detectors. 

Size selectivity can depend on size like in case of relatively tiny sodium channel letting small sodium ion through but not larger potassium or calcium. Potassium channels have different mechanisms as they don't let smaller sodium through. Ions like sodium and potassium both attract water molecules and this group of atoms can behave like larger particle. In potassium channel larger pore reaches water around ion and removes some of it but can't do it for water around smaller sodium. Suspected mechanisms include oxygens in C=O groups stabilizing potassium to stay in channel while sodium wouldn't be stabilized and is unlikely to pass narrow tunnel (potassium channels have about 1/10 000 chance of letting sodium through instead of potassium). As channel could fit few potassium atoms it is also possible that they repulse each others and push each other out of the channel giving it maximum ion flow of up to 100 million potassium ions per second (in neurons opening for about 1 millisecond). One additional possible factor is that helical proteins have charged areas in predictable areas. In loops of helices oxygens are on the side towards C terminus of protein and NH are towards N terminus. This creates repeating rows of H, N and O that could attract positive ions in that sequence as electronegativity determines which atoms gets what charge and after that electrostatic interactions start to work on ions. Voltage sensing in potassium channels is controlled by charged glutamine acids and lysines which attract to side of cell suitable for their charge and distort potassium channel in process. Common potassium channels on neurons open only if inside of cell becomes positively charged.

Sodium channel pore parts have mainly negatively charged amino acids and mutations that reduce negative charge there slow the flow of sodium through the channel. Replacing weakly positive lysine (this amino acid could behave like negative charge to calcium due to electronegativity of hydrogen and nitrogen making them pull electrons from calcium) or uncharged alanine with glutamine acid make sodium channel behave more like calcium channel. 
Chlorine channel in E.coli has 3 binding sites for chlorine atoms. At least outermost of these sites can attract carboxylic group from glutamine acid and block the ion channel.

Calcium channel can let sodium through more easily if negatively charged glutamine acids in certain locations (one of 3 seems enough) gets replaced by uncharged glutamine or alanine. At least 3 glutamine acids line inside of calcium channels and seem to participate in selectively letting positive ions through.

Proton channels are so selective to H+ ions that in that study authors didn't detect other ions getting through it. When they replaced aspartic acid with similarly charged glutamic acid it stayed selective to H+ but when Asp was replaced with uncharged amino acid the channel stopped conducting ions or was letting selectively negative ions through.

Ion channels tend to be covered with sugar type molecules (glycosylated) and amount of glycosylation influences sensitivity to voltage.

Possible reason why channels need those could be because sugary substances like syrups and starch create viscous goo that slows down flow of fluid. Even mucus proteins seem to get their gooey consistency from glucose type additives on it's protein chain. 
For proteins this slowdown means that charged particles don't fly by so fast and leave more time for their electric charges to pull-push other charges around.    
Calculator for finding how fast is molecule or atom with chosen mass on chosen temperature. At body temperature sodium have average speed of 470 m/s (1700 km/h). Water is about 10% faster than sodium. Water freezes if its molecules are slower than 502 m/s at 0 C and boil at 587 m/s with electrostatic attractions in form of hydrogen bonds keeping ice or liquid water together at these speeds. Overall water and ions move about 1 m/s (~3 km/h) per each degree C. Calcium and potassium are have speeds of around 350 m/s or 1290 km/h. At such sometimes supersonic speeds ions don't leave each other much time to react to each others charges. In liquid water particles are still fast but they keep attracting each others and also collide often which slows average observable speed to what can be seen with color diffusing through water. By adding slimy consistency particles slow down even further and leave electric attractors or repulsors in proteins or artificial nano-devices more time to push-pull ions in predictable way.