Peter Csermely
Semmelweis University, Budapest, Hungary
A network scientist highlights active sites of enzymes, cells, brains and society.
For proteins, chemical binding is a tricky business. Special signals must be sent across a sea of water molecules to the desired partner, and complex mutual structural adjustments (a fluctuation fit) must be completed before each successful binding event.
I have long taught that a protein at its lowest-energy conformation still has regions of higher energy. But I've always been intrigued: how is the extra energy of the active sites preserved? And why do we need such big enzymes when their active sites occupy only a tiny region?
Piazza and Sanejouand found part of the answer by identifying special energy-preserving segments of proteins (F. Piazza and Y.-H. Sanejouand Phys. Biol. 5, 026001; 2008). Taking into account the effect of the surrounding water, they modelled proteins with a computer program that arranges oscillating elements in the same pattern as amino acids in real proteins. In most of these proteins, they identified a few easily excitable segments that collected and harboured long-lived, localized vibrations. An analysis of 833 enzymes showed that these segments co-occur with the catalytic active sites; are located on the stiffest parts of the proteins; and have many connections but are surrounded by a less well-connected environment.
The generality of many network properties prompts me to ask: can we find 'active sites' of cells, brains, ecosystems and societies? Piazza and Sanejouand's segments correspond to Ronald Burt's "structural holes" in social networks — whereby areas of greatest economic potential are areas of low connectedness, where brokers can make new connections. Indeed, not only amino acids, but people may also act as brokers, mediators and catalysts. It may be worthwhile to think about creative, broker proteins as drug targets. One could even imagine creative sets of neurons.
Comments
Several readers of the Journal Club Column asked me the question: what do I mean under "active sites of cells, brains, ecosystems and societies". This prompted me to extend the idea, and summarize the properties of creative elements, i.e. those network elements, which may play a key role in the development, inheritance and regulation of evolvability of complex systems. Please find this extension of the Journal Club Column ideas here: www.arxiv.org/abs/0807.0308 I would greatly appreciate your comments for that as well.
Posted by: Peter Csermely | July 4, 2008 12:49 PM
Dear Csermely
really I prefer my dear Peter,
I am feeling that you and I are equally open-minded scientists.. You have wrote as incipit: "For proteins, chemical binding is a tricky business. Special signals must be sent across a sea of water molecules to the desired partner, and complex mutual structural adjustments (a fluctuation fit) must be completed before each successful binding event". Knowing Quantum Biophysical Semeiotics (See my website, and also in www.nature.com at these URLs: http://blogs.nature.com/nature/journalclub/2008/06/seth_lloyd.html#comments
http://blogs.nature.com/news/thegreatbeyond/2008/06/weekly_round_up_39.html#comments
http://www.nature.com/news/2008/080130/full/451511a.html?q=2#last-comment
http://network.nature.com/forums/harvardpublishingforum/1832?page=1#reply-4955
www.nature.com , http://www.nature.com/news/2008/080130/full/451511a.html
http://www.nature.com/news/2008/080515/full/news.2008.829.html), real events are more complex, i.e., difficult to understand, than generally admitted today. However, the preence of no local realm besides local realm in Biological Systems, I discovered (bibliography in may website), higlights the patho-physiological mechanisms underlying above-mentioned events. As I illustrated also in The Lancet.com (Stagnaro Sergio. The Lancet, January 28, 2008. Bedside Biophysical-Semeiotic Osteocalcin Test in Diagnosing and Monitoring Diabetes.
http://www.thelancet.com/journals/lancet/article/PIIS0140673608601014/comments?action=view&totalComments=2
; Stagnaro Sergio. Il test Semeiotico-Biofisico della Osteocalcina nella prevenzione primaria del diabete mellito. www.fce.it Febbraio 2008. http://www.fcenews.it/index.php?option=com_content&task=view&id=909&Itemid=47) osteocalcin , and all other hormones, act upon the related receptors in two diverse action mechanisms: fist of all, simultaneously, due to EI (Energy Information), according to Paolo Manzelli (ibidem), and secondly by that manner sufficiently known all around the world, that you in facinating way have underlined in your intriguing paper.
My compliment!
Posted by: Sergio Stagnaro MD | July 8, 2008 09:29 AM
Dear Sergio,
thanking for your extensive references I have to admit that non-local interactions are, indeed, one of the most difficult areas of current science. Why?
First, we are rather far from understanding the web of weak links (low affinity, transient interactions, see e.g. my Springer book: http://www.linkgroup.hu/petercsermelyweak.php ), which may non-obviously transmit a number of signals for a far distance.
Second, we have an even smaller experience in the methodology of assessing the resonance-type effects, i.e. the amplifications of propagating perturbations in special points of a complex system (see e.g.: http://arxiv.org/abs/0802.2330 ).
Lastly, we have a very limited knowledge on the synchronization of oscillations, especially, if the oscillations are at different levels of complexity (e.g. the synchronization of amino-acid side chain vibrations with waves of protein conformational changes and cyclic cellular behaviour). Does such a multi-level synchronization ever happen? We do not even know that yet. Can we extend this phenomenon to the synchronization of excitation of human neurons of different persons, even in a crowd of thousands? Currently we have -- yet -- very limited means to measure this. Let's hope this will change soon.
Indeed, the entanglement of quantum mechanics offer a plausible ground of analogies to explain the above scenarios. However, if we jump more than one levels of complexity in self-organized matter, we often loose the applicability of laws and phenomena of the lower level to the higher one. I am very much afraid this is the case of applying the rules of quantum mechanics to systems of much higher complexity.
Posted by: Peter Csermely | July 9, 2008 10:48 AM