Discussion U. Ryde Paper: Do Quantum Mechanical Energies Calculated for Small Models of Protein-Active Sites Converge?

We discussed the paper by Hu et al.

Bottom line:

• The paper discusses how the energy difference between an HIP state and an HID state is affected by the residues included in the respective model
• Let $E_B$ be the energy of the product state HIP for system $s$
• Let $E_A$ be the energy of the reactant state HID for system $s$
• Let $E_B'$ be the energy of the product state HIP for a system ($s$ + residue $i$), called $s'$
• Let $E_A'$ be the energy of the reactant state HID for a system ($s$ + residue $i$), called $s'$
• Reported is the $\Delta \Delta E := (E_B' - E_A') - (E_B - E_A)$
• Vacuum calculations are essentially worthless because even if the size of the system is set such that the difference in energy appears converged (above 15 residues, Fig. 2, 4, 5), still the energy differences obtained from such a system can change dramatically, once charged residues are added on top of this system (Fig. 7)

• This is less dramatic but still present when using continuum solvent models ($\epsilon =4$), Fig. 7
• It is now a question how much this effect could be further reduced with a higher dielectric constant
• It is however also possible that once the system reaches a certain size, the specific value of the dielectric constant does not affect the energy difference any longer (p.11796)
• One conclusion is that only including every position avoids convergence difficulties due to system size
• This however then most likely requires QM/MM approaches or linear scaling techniques
• If the study is to be carried out using only fragments of the protein back bone, charged residues should be included only together with their counter charge pair if available
• Charged residues in the interior of the protein are usually in counter-ion pairs
• Quantum only studies as the one presented however remain useful in mechanistic studies where one mechanism can be ruled out in favor for another mechanism because their respective activation energies are very different
• For such studies, it is recommended to include only a minimum model consisting of the groups immediately involved in the reaction

Naturvidenskabelig schweizerkniv præsenteres i ny bog

Københavnerkemiker vil udbrede  matematisk universalværktøj

Det er de færreste værktøjer, der både kan slå søm i, skære brædder op og måle dæktryk. Men en kemiker, en fysiker og en datalog har netop offentliggjort en hel bog med matematiske universalværktøjer, der spreder sig over så bred en anvendelsesvifte. Mindst.

 

 

 

 

 

Smal bog henvender sig til bred læserskare

Bogen ”Symmetry-Adapted Basis Sets: Automatic Generation for Problems in Chemistry and Physics” lyder smal og nørdet. Og det er den også. Men ikke mere smal end at den henvender sig til både kemikere, elektroingeniører, brobyggere, meteorologer og alle andre, der beskæftiger sig med at forudsige naturvidenskabelige fænomener med matematisk modellering.

Om de matematiske lighedspunkter mellem guitarspil og kvantekemi

Den ene af forfatterne, Sten Rettrup, har undervist i kemisk teori på Københavns Universitet i mere end 30 år og han er ikke i tvivl. Symmetri er et matematisk værktøj, der kan bruges på noget nær alt.
”Om en differentialligning beskriver et kvantemekanisk system eller en udvikling i vejret gør egentlig ikke den store forskel. Matematisk set er der store lighedspunkter mellem guitarspil og kvantemekanik, når man vil beskrive hvad der sker”, siger kemikeren, der mener at ”Symmetry-Adapted Basis Sets” udfylder et hul i litteraturen om anvendelsen af symmetri.

En mere global tilgang til beregninger gør værktøjer universelle

I modsætning til sædvanlige gruppeteoretiske metoder beskriver bogen en simplere metode, som udnytter computerteknikker.

”Hvis du går ind på et hvilket som helst universitetsbibliotek kan du finde en halv kilometer bøger om symmetri. Men de beskriver ofte den matematiske anvendelse til at håndtere ét specielt hjørne af naturvidenskaben. Vi tager udgangspunkt i, at de samme værktøjer i bund og grund kan bruges i alle skalaer”, forklarer Rettrup.

Styrke at forfatterteamet kommer fra hver sin matematiske kultur

Som kemiker, forsker og underviser erkender Sten Rettrup at hans navn mest er kendt for den beskrivelse af symmetri, der kaldes gruppeteori. Det er et hjørne som er altafgørende når man arbejder på molekyleniveau med kvantemekaniske beregninger. Men Rettrups medforfattere kommer fra to helt andre matematiske kulturer.

John Scales Avery er først og fremmest matematisk fysiker, mens den tredje forfatter, James Emil Avery, er uddannet datalog. Takket være de tre forskellige tilgange er ”Symmetry-Adapted Basis Sets” blevet til et muligt opslagsværk uanset hvilken form for naturvidenskabeligt fænomen man gerne vil modellere. Fra elektronstrukturer af atomer og molekyler til varmeledning og akustik. Og altså vejr, vind og konstruktioner. Dermed kan bogen blive et værdifuldt bekendtskab for både fysikere, kemikere, ingeniører og… Nå ja. Matematikere.

”Vi præsenterer helt enkelt en række idéer til, hvordan man kan tackle og angribe beregningsproblemer. Især på store komplekse problemer. Jeg vil påstå, at der næppe findes et eneste naturvidenskabeligt område, hvor symmetri ikke kan bruges til at modellere problemerne”, slutter den bogaktuelle teoretiker.

SYMMETRY-ADAPTED BASIS SETS

Automatic Generation for Problems in Chemistry and Physics

Fås som papir og Ebog hos World Scientific Publishing Co.

Source

Some things I learned about using Google+

These things might be obvious to everyone but me, but:

1. Unless you share posts as "Public" your posts will be invisible to people who have you in their circles, but who you do not have in your circles.  Also, only then will your posts be discoverable on the web. 

2. Unless your post is "Public" it can not be shared publicly.

3. If a post has been shared publicly you can "View Ripples" in the option menu, which is very cool.

So, unless you work for the CIA and use Google+ extensively for work, most of your posts are probably best posted as "Public". Finally,

4. If you add a person explicitly (using +name) anywhere in the post, that person will be notified about the post.  This is handy if you are not in that person's circles, or if you simply want to make sure that person sees it.  Also, if you only type that persons name (i.e. do not choose "Public" or any circle) then it's basically like a private email message.

New paper: A Computational Methodology to Screen Activities of Enzyme Variants

Martin just submitted his paper to PLoS ONE and deposited it at arxiv.org/abs/1203.2950.

PM6 is a qualitative step forward for semiempirical methods ability to predict correct reaction mechanisms and hydrogen bonding geometry.  Given the computational speed of PM6 this means that barrier heights now can be estimated very efficiently for large systems such as enzyme-catalyzed reactions. In this paper we present a computation methodology that does just that, and use it to screen for mutants that lower the barrier height.   As far as I can tell this is the first method that can do that.

Abstract
We present a fast computational method to efficiently screen enzyme activity. In the presented method, the effect of mutations on the barrier height of an enzyme-catalysed reaction can be computed within 24 hours on roughly 10 processors. The methodology is based on the PM6 and MOZYME methods as implemented in MOPAC2009, and is tested on the first step of the amide hydrolysis reaction catalyzed by Candida Antarctica lipase B (CalB) enzyme. The barrier heights are estimated using adiabatic mapping and shown to give barrier heights to within 3kcal/mol of B3LYP/6-31G(d)//RHF/3-21G results for a small model system. Relatively strict convergence criteria (0.5kcal/(mol Å)), long NDDO cutoff distances within the MOZYME method (15 Å) and single point evaluations using conventional PM6 are needed for reliable results. The generation of mutant structure and subsequent setup of the semiempirical calculations are automated so that the effect on barrier heights can be estimated for hundreds of mutants in a matter of weeks using high performance computing.

Seminar: Protein folding on the ribosome

Protein folding on the ribosome

Dr. John Christodoulou, University College London

Biocenter seminar room (1-2-03) at 15:00

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Recent publications from Dr. Christodoulou include:

Solution-State Nuclear Magnetic Resonance Spectroscopy and Protein Folding
Cabrita, L.D., Waudby, C.A., Dobson, C.M., Christodoulou, J.
Methods in Molecular Biology (2011) 752, 97-120

GPU accelerated Monte Carlo simulation of pulsed-field gradient NMR experiments
Waudby, C. A., Christodoulou, J.
Journal of Magnetic Resonance (2011) 211, pp 67-73

New Scenarios of Protein Folding Can Occur on the Ribosome
O’Brien, E.P., Christodoulou, J., Vendruscolo, M., Dobson, C.M.
Journal of the American Chemical Society (2011) 133, pp 513–526

Protein folding on the ribosome
Cabrita, L. D., Dobson, C. M. & Christodoulou, J.
Current Opinion in Structural Biology (2010) 20, pp 33–45

Probing ribosome-nascent chain complexes produced in vivo by NMR spectroscopy
Cabrita, L. D., Hsu, S.-T. D., Launay, H., Dobson, C. M. and Christodoulou, J.
PNAS (2009) 106 pp 22239–22244

You can read more about Dr. Christodoulou's research on his website: http://jcgroup.biochem.ucl.ac.uk/people/john/.

Infinite Recursions Through Posters

Somehow this picture(from my first stay in Japan) was on a poster about
education at the department of Chemistry at the university of Copenhagen.

Have a nice weekend

(see full image)

Casper

Apps can make you smarter

I was interviewed by the the popular science site videnskab.dk on using iPad apps in research an education (in Danish).