Genome, Proteome and the Quest for a Full Structure–Function Description of an Organism

Abstract

Abstract Completion of the Human Genome Project provided the deoxyribonucleic acid (DNA) sequence of a human genome – a complete blueprint of our organism. Genomic information is processed into ribonucleic acid (RNA) and then into proteins, which carry out most cellular processes that sustain life. All of these molecules – DNA, RNA and proteins – have unique three‐dimensional shapes, and the atomic details of these shapes, and the inherent information they carry, define their function. Every cell, and ultimately the entire organism, may be viewed as a gigantic three‐dimensional jigsaw puzzle where all of the pieces have to fit together for the whole system to function. Elucidating the shapes of the molecular elements of the cell helps decipher the rules that dictate how they hierarchically form larger objects, such as molecular machines, organelles, cells and organs, how the shapes of individual molecules and their assemblies change on regulation, what changes cause disease and eventually, how they can be repaired or how they can be targeted by drugs. Key Concepts: Genes are coded in a four‐letter code by linear strings of DNA and define sequences and shapes of all downstream products (RNA and proteins). DNA has a limited number of three‐dimensional shapes that it can take (three main forms currently known), but even small variations of these shapes are important for gene regulation and interactions between DNA and other molecules. Products of DNA transcription (RNA) and translation (proteins) have complex but unique three‐dimensional shapes that are defined by their sequence and post‐translational modifications as well as interaction with other molecules. Experimental determination of DNA, RNA and protein three‐dimensional structures by X‐ray crystallography, NMR spectroscopy and other techniques provide a molecular level understanding of the fundamental processes of life. The number of basic shapes (or folds) that RNA and proteins can adopt are limited by steric constraints; however, these numbers are very large as compared to the limited number of DNA shapes – it is now known hundreds (RNA) or thousands (protein) of shapes and (probably) thousands of other shapes are still possible. Regulation of DNA, RNA or protein function often involves changes to their structure and/or dynamics. DNA, RNA and protein molecules form functional networks where neighbours in the network influence and regulate each other. Analyses and simulations of such networks is a subject of systems biology, which ultimately provides a perspective for predictive modelling of biological systems. DNA, RNA and protein molecules can form higher order complexes and assemblies – a process driven by a mutual compatibility of their shapes and/or chemical composition. Such complexes define the many nodes in functional cellular networks. Experimentally determined structures of DNA, RNA and protein complexes and assemblies provide a detailed picture of how regulation of cellular processes is carried out.