Grant: Discovery Grants Program - Individual

The mitochondrion is a complex and compartmentalized eukaryotic cell organelle responsible for cellular respiration in a multicellular organism that is, burning foodstuffs to produce the energy necessary for sustaining life. It consists of an inner matrix (the location of the Kerbs cycle) enclosed by two membranes: An outer smooth and permeable membrane, and an inner corrugated and highly selective one. The inner membrane hosts an array of connected chemical reactions that use the energy released in exergonic electron transfers to pump protons out of the matrix and into the gap between the membranes. This proton imbalance is equivalent to stored energy due to the combined concentration and electrical gradients. When protons re-enter the matrix this energy is released. If the protons re-enter through a ""leak"" in the membrane (e.g. due to uncouplers), the released energy is dissipated as heat and the cell gains nothing. To sustain life (by producing ATP), the protons must re-enter through a specific channel within ATP-synthase which captures the energy to drive the endergonic reaction ADP+Pi--> ATP. The proposed research has two broad goals: (a) Discovering some aspects of the rich chemistry that happens inside the inner mitochondrial membrane using the modern tools of quantum chemistry, and (b) use the mitochondrial systems to develop, test, and improve emerging methodologies in applied quantum chemistry. With regards to (a), several aspects of inner mitochondrial membrane biochemistry will be explored computationally, for example, the effect of the strong electric field across the membrane on the reactivity of membrane-bound species and its relation to the production of the superoxide radicals implicated in accelerating cell damage, degenerative diseases, and programmed cell death. With respect to (b) there are two sub-branches. The first is to improve and broaden the applicability of a recently proposed molecular fingerprinting tool by predicting the properties of uncouplers with known activities in quantitative structure-activity relationship (QSAR)-type studies. Second, the reconstruction of approximate ab initio quality electron density and electrostatic potential of a gigantic protein, namely, ATP-synthase, the (partial) low resolution (9 A) structure of which has just been published. This structure will first be completed through homology modeling and the careful consideration of chemical constraints. To start, the missing amino acids and missing atoms will be added followed by force field geometry optimizations. The refined geometry will then be used to define the necessary kernel fragments that will be combined to reconstruct the electron density and electrostatic potential of the entire protein at an ab initio level, approximating in months elusive exact results that, in principle, should take more than the age of the Universe to calculate with present-day computers.