Almost - the water molecules bind stronger to sodium because their oxygens get closer to the positive charge. This makes it impossible to tear off those waters at the selectivity filter.
Hi@alex_vassilevski@hotmail.com Vassilevski. First, if you have a question, feel free to ask. Second, it's definitely possibly that I misspeak in videos or write incorrect comments, but the way to behave in that case - provided you want to retain the privilege of making comments here - is to politely ask about it, and the same goes when you make comments about other commenters here (and likely most other settings too). Having said that, you are mostly right about the conduction. The part forming the selectivity filter is merely unstructured in the sense that it does not have a helix/sheet secondary structure (this is why it's called the P-loop), but as the four subunit comes together - and binds ions there - it is both rigid and structurally well defined. It's also correct that it's the backbone carbonyls (in the TVGYGD P-loop sequence) that face the narrow pore, but that per se does not contradict the helix dipole contribution to help strip off hydration water (if you think it does, read Rod McKinnon's 1998 science paper where he describes both the P-loop and and helix dipole stabilisation model for the first time; this is the work for which he was awarded the 2003 Chemistry Nobel Prize). Dan Minor has argued that the helix dipole effect is smaller at least in Kir2.1, which is an interesting observation, but this far I'd still say MacKinnon's model has pretty broad support. And, to avoid any other confusion about things I don't say explicitly, the ion is definitely still hydrated in the internal cavity where the cobalt ion is depicted here; it's only when it goes from the internal cavity into the selectivity filter that hydration water has to be released. So, how does one reconcile the coordination inside the selectivity filter with that? First, when it comes to the hydration of Na+ vs K+ that too is an educating question. Historically we like to think of hydration "shells", which are mostly defined by steric packing combined with H-bonds, but strictly speaking the only relevant part both for hydration and reaction kinetics is energies and energy barriers (although those are of course related to the number of waters). So, interestingly the two statements are not contradictory: Na+ definitely has fewer hydration waters than K+, but it's hydration *free energy* is roughly -405kJ/mol, while K+ only has around -320kJ/mol, and as we've learnt in this class, what happens or not in the world is defined by free energy. To actually conduct a particular type of ion two things are requires: 1. The ion must be electrostatically stabilised in the region where it does not have its hydration water 2. The ion must be able to move into that region (i.e., shed hydration water) without encountering an excessive free energy barrier There are quite a few studies that have shown the dimension of the selectivity filter in KcsA and related channels is optimal to stabilise K+. This explains #1, but to actually reach these sites in the first place the ion also needs to have a pathway where it is stabilised while the hydration waters are gradually released, without having to pass a very high free energy barrier, and this is where Rod's original helix dipole model entered (and which was later supported in calculations by Toby Allen & Crina Nimigean). Exactly how the extremely effective conduction and selectivity happens on the molecular/quantum mechanical levels is still a matter of some debate, with Benoit Roux and Bert de Groot (and some others) arguing about both pore flexibility and knock-on effects between ions (An interesting side point is that there are also nonselective NaK channels with an almost-identical selectivity filter). Both are dear friends and great scientists, so instead of siding with one of them, I'll just recommend reading both their papers - but also take all these computational results with a big grain of salt, because they are models, not settled science. So, my apologies if you would have liked more detail, but in summary I think the ion hydration free energy combined with the helix dipoles and selectivity filter is a beautiful simple model that explains how it's possible to achieve selectivity that is the opposite of radii in the periodic table of elements. That does not mean more elaborate models are wrong, but in particular in a class I much prefer the 60-second explanation that does not require digesting a bunch of MD simulation papers first :-)
Woah! I just discovered how amazing these lectures are. As a first year PhD student currently taking mol bio class, I'm eternally thankful!
Very well explained, comprehensive and nicely illustrated.
Could not have asked for a better introduction to the principles of Potassium slectivity.
You’re an awesome teacher!
very helpful explanation, thank you!
So the reason why sodium cannot go through this channel is because it has more water molecules surrounding it than K+?
Almost - the water molecules bind stronger to sodium because their oxygens get closer to the positive charge. This makes it impossible to tear off those waters at the selectivity filter.
Hi@alex_vassilevski@hotmail.com Vassilevski. First, if you have a question, feel free to ask. Second, it's definitely possibly that I misspeak in videos or write incorrect comments, but the way to behave in that case - provided you want to retain the privilege of making comments here - is to politely ask about it, and the same goes when you make comments about other commenters here (and likely most other settings too).
Having said that, you are mostly right about the conduction. The part forming the selectivity filter is merely unstructured in the sense that it does not have a helix/sheet secondary structure (this is why it's called the P-loop), but as the four subunit comes together - and binds ions there - it is both rigid and structurally well defined. It's also correct that it's the backbone carbonyls (in the TVGYGD P-loop sequence) that face the narrow pore, but that per se does not contradict the helix dipole contribution to help strip off hydration water (if you think it does, read Rod McKinnon's 1998 science paper where he describes both the P-loop and and helix dipole stabilisation model for the first time; this is the work for which he was awarded the 2003 Chemistry Nobel Prize). Dan Minor has argued that the helix dipole effect is smaller at least in Kir2.1, which is an interesting observation, but this far I'd still say MacKinnon's model has pretty broad support. And, to avoid any other confusion about things I don't say explicitly, the ion is definitely still hydrated in the internal cavity where the cobalt ion is depicted here; it's only when it goes from the internal cavity into the selectivity filter that hydration water has to be released.
So, how does one reconcile the coordination inside the selectivity filter with that?
First, when it comes to the hydration of Na+ vs K+ that too is an educating question. Historically we like to think of hydration "shells", which are mostly defined by steric packing combined with H-bonds, but strictly speaking the only relevant part both for hydration and reaction kinetics is energies and energy barriers (although those are of course related to the number of waters). So, interestingly the two statements are not contradictory: Na+ definitely has fewer hydration waters than K+, but it's hydration *free energy* is roughly -405kJ/mol, while K+ only has around -320kJ/mol, and as we've learnt in this class, what happens or not in the world is defined by free energy.
To actually conduct a particular type of ion two things are requires:
1. The ion must be electrostatically stabilised in the region where it does not have its hydration water
2. The ion must be able to move into that region (i.e., shed hydration water) without encountering an excessive free energy barrier
There are quite a few studies that have shown the dimension of the selectivity filter in KcsA and related channels is optimal to stabilise K+. This explains #1, but to actually reach these sites in the first place the ion also needs to have a pathway where it is stabilised while the hydration waters are gradually released, without having to pass a very high free energy barrier, and this is where Rod's original helix dipole model entered (and which was later supported in calculations by Toby Allen & Crina Nimigean).
Exactly how the extremely effective conduction and selectivity happens on the molecular/quantum mechanical levels is still a matter of some debate, with Benoit Roux and Bert de Groot (and some others) arguing about both pore flexibility and knock-on effects between ions (An interesting side point is that there are also nonselective NaK channels with an almost-identical selectivity filter). Both are dear friends and great scientists, so instead of siding with one of them, I'll just recommend reading both their papers - but also take all these computational results with a big grain of salt, because they are models, not settled science.
So, my apologies if you would have liked more detail, but in summary I think the ion hydration free energy combined with the helix dipoles and selectivity filter is a beautiful simple model that explains how it's possible to achieve selectivity that is the opposite of radii in the periodic table of elements. That does not mean more elaborate models are wrong, but in particular in a class I much prefer the 60-second explanation that does not require digesting a bunch of MD simulation papers first :-)
amazing lecture, thank you!
Thank you
thank you :)