September 24, 2009

To Unfold The Secret of Protein Folding, Foldit!

Genes in living cells dictate the cellular machinery to form proteins, the ultimate product of genetic information that is encoded in the DNA. These proteins perform various functions in the body. Some maintain the structure of the cells, some act as enzymes thereby catalyzing reactions, some act as pumps and ion channels thus maintaining ionic equilibrium and events like muscle contraction and action potentials in neurons, some act as receptors which recognizes ligands and binds them and so on.

However, genes merely determine the sequence of amino acids in the protein. These amino acids form the primary structure of proteins by joining themselves by peptide bonds, just as different colored beads make up a string. Some amino acids in the protein undergo post-translational modification such as carboxyllation, phosphorylation, once the primary structure has been determined. Then the protein folds in such a way that it is most stable in the tissue conditions like pH etc. Indeed, living tissues try to make order (stable protein configuration) out of seeming disorder (random amino acids) in an apparent violation of the second law of thermodynamics.

Folding also saves valuable space. But why and how should the protein fold? There are interactions between amino acid residues in the form of covalent bonding such as disulfide bonds; non covalent interactions like hydrogen bonding (between hydrogen and oxygen atoms in the peptide backbone), electrostatic or salt bonds between oppositely charged residues, and hydrophobic interactions whereby hydrophobic (water hating) portions of the molecule stay away from water. So, the protein folds to a conformation where the conflict is kept to a minimum. X-ray crystallography, NMR spectroscopy, computational biology and atomic force microscopy are useful tools in elucidating protein structure. Although the way it folds has been simulated in the computer, having humans do it as a computer game and then trying to figure out how the computer did so is surely worth trying. That’s where Foldit comes in.

I first knew of Foldit about a week ago in the print version of the August edition of HHMI Bulletin. screenshot of the computer game Foldit for insights into protein foldingAfter a user downloads the program and installs it, he can see proteins as multicolored structures. All he has to do is to grab the mouse, then pull, twist and wiggle the structure so that it has the most optimal position using the mouse. The program will give you a hint should the atoms be too close or if the hydrophobic ends are sticking out. The program relies on the pattern recognition ability and visuospatial scratchpad (of the working memory) of individuals. Intuition plays a big role and thus scientists may not be much good at this game. The ABCs of Foldit are Apart(sidechains), Buried (hydrophobic domains) and Compact (protein).Users could also play online so that their scores were kept on the servers, and collaborated with each other evolving the game further (Online Darwinism?) Persons having exceptional folding solving abilities are aptly called 'foldit savants', possibly deriving its name from 'idiot savants', persons belonging to the autism spectrum but having extraordinary abilities in certain subjects like mathematics. Albert Einstein was thought to be autistic.

Previously I have used Wolfram’s Mathematica and NanoCAD written by my friend Will Ware. NanoCAD is indeed an outstanding tool, given that it was programmed more than 10 years ago. The basics of NanoCAD and Foldit look rather similar to me, only the complexity and online participation is differing.

Anyway, you always win because you are playing for a cause. A definite and stable protein structure prediction might help researchers the right antibody, the right vaccine, develop better drugs with little side effects and so on. Who knows if this paves the way for the treatment of Alzheimer’s disease, cancer or AIDS?

Since this game exploits intuition rather than intellect, we could perhaps also measure hemisphere dominance in the participants. The effects of psychotropic drugs on game performance could also perhaps be measured.

As of me, I could not play above a certain level. My CPU usage, as shown in the task manager was 100%.
P.S. I still use a Celeron 1.2 GHz CPU and have only 256 MB SD RAM. I could not connect with the server as well.

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