In-silico drug design

This is the estrogen receptor. Women typically have a lot of the swimming around in their cytosol. Once estrogen binds, the complex moves to the DNA and transcription of the corresponding genes start.

In this picture there is only the ligand binding domain. They couldn't crystallise the whole protein because it was too flexible. Instead of showing different domains they chose to show the same domain three times. Alright: it's because of the crystallisation and XRD technique. The unit cell happens to have 3 unique molecules.

The small green things are the estrogens bound to their respective estrogen receptors. If you are trying to find a new drug that targets the receptor, these so called ligands and their binding sites are the most interesting part. The goal of in-silico drug design is screening a large library of molecules to find different molecules that also bind to a given receptor.

If you don't know what the structure of a protein looks like but you have the structure of similar proteins, you can go for homology modeling.

Once you have the structure of the binding site you try to dock ligands that will probably fit in your structure. First you have to find the right geometry of the ligand. After you have done that you have to score the docking, i.e. estimate the change in free energy of the docking process. This is rather difficult because there is no zero point energy to compare your docking pose with and because you have to include entropic effects.

Electrochemistry (2)

Alright, electrochemistry (2) is coming up. Time to write about fuel cells. They are some pretty cool stuff in my opinion. And they are the most important research area in electrochemistry.

The net reaction taking place is pretty basic:
H₂ + 1/2 O₂ -> H₂O
You may probably have heard it before.

Other types oxidise hydrocarbons or alcohols with air oxygen. An important example is the direct methanol fuel cell that this lady at BBC likes to use to power her cell phone.


Using the reaction above for the production of electricity is not quite simple. The trick is that you need an electrolyte that conducts either H⁺ or O^2-.

If you want to conduct H⁺, the polymer electrolyte membrane fuel cell is your choice. The electrolyte is Nafion an ion exchange membrane based on teflon with sulfonic acid groups. Nafion only lets small cations pass (which is kind of opposite to typical ion exchange). With the help of platinum, hydrogen is stripped of its electrons at the anode. It travels through the Nafion membrane. It reacts with oxygen at the cathode and regains its electrons to form water. The PEM works at 80°-90°C.

You can also have the O^2- move around. One way to have that is ZrO₂ doped with Y₂O₃. Next to the yttriums there are oxygen vacancies. At 700°-1000°C its conduction is good enough for use in the solid oxide fuel cell. The solid oxide fuel cell is nothing for your cell phone, rather for a small power plant with good efficiency, especially combined with a Carnot process.

A third type is the molten carbonate fuel cell (300°C). Oxide ions combine with CO₂ to from carbonate. Carbonate travels through the fuel cell. CO₂ is released at the anode.

Alright that's it for now. I like my internship but coding in Python all day doesn't really make you want to sit in front of your computer after coming home.

Electrochemistry (1)

I just had my electrochemistry exam. So I thought it's a good idea to give a quick summary over modern batteries and fuel cells. Both are systems that use spontaneous chemical reactions to generate electricity. Fuel cells work continuously, batteries discontinuously.

For every electrochemical process there are four components that have to be considered: anode, cathode, electrolyte, electron conductor. "Red cat" tells you that reduction occurs at the cathode.

Probably the most important secondary (i.e. rechargeable) cell ist the lithium ion battery. You find it in pretty much every cellphone or portable computer. If charged the anode consists of anionic carbon (LiC₆) and the cathode of lithium-cobalt(III/IV)-oxide (LiCo₂O₄). Both of those don't sound very stable. In other words we have a high voltage (about 3.5V). With high voltage and low density components the lithium ion battery has a very high energy density.

There is no way to use water in such a system (it decomposes at 1.2V). Instead ethylene-carbonate with LiPF₆ is taken (large PF₆^- means low lattice energy and therefore good solubilty even in an organic solvent).

The two half-cell reactions are:

anode: LiC₆ -> C₆ + Li⁺ + e^-
cathode: LiCo₂O₄ + Li⁺ + e^- -> Li₂Co₂O₄

Lithium goes through the electrolyte, the electron goes through the conductor (and your cell phone). They meet at the cathode and reduce Co(IV) to Co(III). The nice thing is that Li⁺ just intercalates back and forth without altering the electrodes. This "rocking chair" mechanism makes recharging possible. Compare this to the various types of lithium batteries containing lithium electrodes. It is not possible to make the electrode appear in its original shape through recharging. Dendrites will lead to short circuits.

Another way to get around dendrite growth is having the electrodes in their molten state. A typical example is the Zebra battery which works at 300°C and gives 2.6V. It has liquid sodium as an anode and NiCl₂ dispersed in liquid NaAlCl₄ as a cathode. The electrolyte is a solid sodium conducting ceramic, e.g. NaAl₁₁O₁₇. Zebra batteries are used in electric vehicles.

A more down to earth method is the nickel-methal-hydride battery (1.2V). We have an alloy hydride (MH) anode, a NiOOH cathode and a KOH electrolyte. Half cell reactions are (the proton is transported via the OH^-):

MH + OH^- -> M + H₂O + e^-
NiOOH + H₂O + e^- -> Ni(OH)₂ + OH^-

Fuel cells maybe tomorrow. Have a happy summer!

Retinal - Ultrafast is just about fast enough

Ultrafast, barrierless processes have the remarkable feature that they occur in less than a picosecond and can therefore be modelled with molecular dynamics. The cis-trans isomerisation of photo-excited retinal is ultrafast. This is not primarily God's grace toward theoretical chemists (who like to model the process) but it ensures that the process is efficient and vision works. [1]

The trick with an ultrafast process is that after excitation, the reaction occurs (almost) without a barrier. The time is determined by the skeletal deformations, cf. a 333/cm vibration has a period of 100 fs.

To understand what is going on, it is sufficient to consider a smaller system than retinal, for example the pentadiene-iminium ion (the N instead of O comes from the protein). The system is strongly polarised toward the N. The first excited state (shwon in red) is polarized the opposite way.

After excitation (γ means "photon" [2]) the cis-doublebond becomes a single bond. Because of that it stretches out. Now there is an ecliptical single bond with weak π-conjugation. It spontaniously rotates.

The crucial step comes now: The excited state decreases in energy as the rotation progresses. The ground state's energy increases. At about 90° torsion angle their energies are the same. This is called a conical intersection. Now a radiationless transition occurs and we are in the ground state again. Ground state means double bond. And that means that a linear alignment is preferred. The molecule can either move back to the cis form or it keeps rotating the same direction and becomes trans. The ratio depends on the exact shape of the potential energy surface.

During that whole process we move down on potential energy surfaces. The geometry is relaxed to a minimum in the excited state. Then the molecule switches to the ground state where it has a local maximum. And the reaction keeps going until we reach one of the stable ground state structures. The energy needed to drive the process comes from the photon. But as soon as the photon is absorbed everything happens spontaneously.

Because of the short reaction time no competing reactions are to be expected. Fluorescence is with 10^-8 seconds 5 orders of magnitude slower. But also collisions that could take up energy aren't likely in that kind of a time frame. That means we can expect high quantum yield. It is 65% for retinal in rhodopsin and 25% for retinal in solution.

The information was mostly from this article by Garavelli (10.1007/s00214-005-0030-z).

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[1] Sorry for making a religious reference in a scientific text. But where I come from the gap between religion and science isn't quite as big. Our religious people don't try to sabotage scientific theories for incomprehensible reasons and our scientists don't announce that they are atheists all the time. I don't know whose fault the situation in the US is. Maybe religious people should be nice and tolerant. Maybe scientists should be smart and on top of things. Maybe it's difficult for anyone to stop a fight once it has that scale and all you can do is defend your own interests.

[2] I don't like the hν for two reasons. First the energy is neither the only feature of a photon (it has momentum, spin, ...) nor is hν a unique identification for it. Second I don't like ν because it looks like a v and it does not abbreviate the word "frequency" like f does.

Rhodopsin

The interesting thing about retinal is its photochemistry. I will talk about that soon. But this is another one of the protein-with-functional-group-picture posts. I still haven't quite realized how nice PyMOL is and I still enjoy making pictures with it. But of course also thanks to Röntgen and Bragg. And Edwards et al. who investigated the structure of this bovine rhodopsin.

This is the subunit with retinal (shown in red). Long stretched helices.

Retinal is bonded to a lysine residue (pink) to form an iminium ion. Or protonated Schiff base as they say if they are trying to confuse me. Retinal fits nicely into the helices. The π-system is almost planar only the double bond in the ring kind of sticks out. The 11-cis-bond (where I don't understand why it is called 11, probably a terpene nomenclature) is behind the green arc.

Carboxylic groups surrounding retinal are important for the charge distribution. You can select them in PyMOL with the following command (after making a selection "retinal" with retinal):

select SurrAc, (retinal around 10) and resn asp+glu

There is one at the iminium group ...

... and one at the β-ionone ring.

They give the molecule kind of a jungle feeling.

Quinine (for real)

I wrote about quinine a while ago. I was told that I had the structure wrong. This is what it should look like.

The difference is the configuration at the stereogenic quinuclidine carbon.

An important difference to the "epi-quinidine" which I drew before is that a hydrogen bond is not possible. In the picture below it can be seen that the -OH and N are bent away from each other.

Rotation around the σ-bond that would lead to an H-bond is not possible for steric reasons.

This is apparent in the spacefill model.

I used the typical programs (I wrote about before) and the Open Babel package that I recently read about at Noel's blog. It's a convient way for converting chemical file types. It was very useful for passing structures between the different modelling and graphics programs.