The curious case of Cytochrome c Oxidase: Role of protein electrostatics in biomolecular structure-function correlation

Nature has created a wide array of fascinating molecular machinery, and their efficiency is unparalleled when compared to their man-made counterparts. Be it photosynthesis (conversion of light into chemical energy), or enzyme catalysis (speeding up difficult chemical reactions), or ion channels (filtration device with high degree of specificity), or self-assembly of small molecules into organized structures, we have a lot to learn from biology! The need for a molecular level understanding of nature has been dramatically asserted by Richard Feynman: Everything that living things do can be understood in terms of the jiggling and wiggling of atoms. Following this ambitious approach, my goal is to understand the complex biomolecular functions and properties from a molecular point of view. Using statistical mechanics based computational techniques, we are able to connect the molecular interactions (energetics) to their structural, thermodynamic and kinetic properties. The ultimate challenge is to obtain the underlying free energy surfaces for any (bio)chemical processes with quantitative accuracy and computational efficiency.
 
In this talk, I shall take up the example of the fascinating molecular machinery involved in the proton transport processes in a trans-membrane enzyme Cytochrome c Oxidase (CcO), which reduces oxygen (O₂) to water in our respiratory cycle and uses the released energy to pump protons across the membrane. I shall discuss the importance of electrostatic interactions, the role of dielectric heterogeneity of the protein interior in affecting the pK_a and protonation state of the key ionizable residues, and the role of internal water molecules therein. We shall demonstrate how molecular thermodynamics can provide physical insights into the function of complex biomolecules.