WEST LAFAYETTE, Ind. – Chemists who have trouble predictinghow some large, complex biological molecules will react with others maysoon have a solution from the world of computational quantum physics,say Purdue University researchers.
Using powerful supercomputersto analyze the interplay of the dozens of electrons that whirl inclouds about these molecules, a team of physicists led by Purdue'sJorge H. Rodriguez has found that the quantum property of electronscalled "spin" needs to be considered to obtain a complete andfundamental picture of how many biochemical reactions take place. Inparticular, a class of metal-based proteins that includes hemoglobinand chlorophyll, and their reactions in plants and animals, can bebetter understood with the technique.
Not only will thisdiscovery sharpen our basic knowledge of biology, Rodriguez said, butit also could help scientists with a number of practical problems –such as selecting the best potential new drug compounds from a vastgroup of candidates, a process that can cost pharmaceutical companiesyears of work and millions of dollars.
"Whereas we have had to besatisfied with observing the chemistry in living things and describingit afterward without complete understanding, we are developingcomputational tools that can predict what will happen between moleculesbefore they meet in the test tube," said Rodriguez, who is an assistantprofessor of physics in Purdue's College of Science. "Not only doesthis research open up a new field of science that reveals howmetalloproteins and their constituent particles interact, but thequantum theory behind it also should allow us to model and predictthese behaviors accurately with computer simulation alone. It is anexample of how much can be accomplished with interdisciplinary science."
Rodriguezis pioneering a new field he calls "quantum biochemistry" – a fieldthat involves both biochemistry and particle physics, which are oftencited among the more formidable subjects science students tackle.Ordinarily, the two disciplines share little common ground. Althoughbiochemistry deals with interactions among the complex molecules thatour bodies use for the fundamental processes of life, thesemicroscopically small molecules are nonetheless gargantuan entities incomparison with the tinier subatomic particles such as protons andelectrons that physicists study.
"Despite these differences,there is one point of overlap between chemistry and physics that hasinterested me, and that is in the elementary particles that whirl aboutthese molecules – the electrons," Rodriguez said. "Physicists have longknown that, according to the laws of quantum mechanics, there are somechemical reactions in our bodies that are 'forbidden' – such ashemoglobin's binding oxygen in our lungs when we breathe. But they dohappen nonetheless. So, because these reactions involve electron spin,we decided to take a closer look at them."
Charge is a familiarproperty of an electron, but it is not the only one. Electrons alsohave another quantum property called spin, and though they are allnegatively charged, they can spin in one of two opposing directions –up or down.
"Nature loves balance, and you see evidence of it inboth charge and spin," Rodriguez said. "For example, electrons ofopposite spin like to pair up with each other as they fly around thenucleus. This allows their spins to balance one another, just aspositive and negative charges do between protons and electrons. Evenwhen you have hundreds of electrons forming an immense cloud around acomplex molecule, you still see balance in both charge and spin; wecall this balance 'conservation,' and it's something we count on inboth chemistry and physics to help us understand these tiny objects.
"Butsometimes the electrons in metalloproteins seem to be playing a trickon us. As we see with hemoglobin, nature appears to be conservingelectronic charge while sacrificing this conservation in spin."
Hemoglobin'sactive center contains iron, one of the so-called transition metals.These metals are noted for the way several of their electrons can flyaround the nucleus unpaired.
When a red blood cell encountersoxygen in our lungs, its hemoglobin is able to grasp some of the oxygenwith some of these unpaired electrons, carrying it to the rest of ourbody. But in the process, the cumulative spin of the system changes ina way that is not conserved, which to a physicist looks as strange as aball hitting the water without making a splash.
"This chemistryis vital for life, but physicists wonder how it can happen," Rodriguezsaid. "The charge between the electrons in the bonded oxygen andhemoglobin is balanced in the end, which makes sense to chemists. Butthe electronic spin of the entire system is not conserved, making aphysicist frown at what appears to be a formally forbidden process. Ofcourse, we needed to learn more about nature at the microscopic level."
Asmany of these supposedly forbidden reactions involve biomoleculescentered upon transition metals, which can flip back and forth betweendifferent spin states under certain conditions, Rodriguez theorizedthat it was this variability in spin state that was influencing therate of these reactions. To explore whether this effect, whichRodriguez calls spin-dependent reactivity, was indeed the decisivefactor, the team is modeling the reaction rates with a supercomputer,the only tool capable of keeping track of the motion of so manyparticles at once.
"Supercomputers have allowed us to check ourmodels against our understanding of spin's effect on a reaction, andour models have been closely checked by experiment," Rodriguez said."The results suggest that our understanding of electron behavior issufficient to create virtual models of molecules that we can then'react' with one another in simulations that accurately predict whatwill happen when they meet in the physical world."
Rodriguez saidthe approach, though still in its nascent stages, could provide insightinto far more biologically important molecules when it is furtherdeveloped.
"We are at the point where we have developedcomputational tools to analyze the spin-dependent processes ofbiomolecules and have applied them to a few important test cases," hesaid. "But our methods are based on approaches that are valid for anymolecular system. Therefore, hundreds more metalloproteins that are ofgreat scientific and practical interest may be studied in the futurewith the methods we have developed."
For example, Rodriguez isplanning to study the manganese involved in photosynthesis tounderstand how water is broken down to produce molecular oxygen. Butfor now, he is happy that the four years of work his team has put intothe project have produced such encouraging results.
"We arecreating a new field that attempts to understand biochemical processesat the most fundamental level – that of quantum mechanics," he said."It could be the most important step toward making biochemistry apredictive science rather than a descriptive one."
Two papers onthe subject, one of which Rodriguez authored with Purdue's TeepanisChachiyo, appear in this week's issue of the Journal of ChemicalPhysics. Jeffrey Long, a professor of chemistry at the University ofCalifornia at Berkeley, commented on Rodriguez's work.
"Rodriguezhas come up with an elegant means of evaluating excited-stateelectronic structures," he said. "It lends insight to the detailedmechanisms of poorly understood transformations in inorganic complexes."
This research has been supported in part by a Career Award from the National Science Foundation.
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