Unravelling the Hydrogen Bonding Patterns in Telomeric G-quadruplexes: From Structure to Function-Paradigm of Aging

The paradigm of aging is now on every-one's lips and thoughts. The cure for aging has long been the Holy Grail of medicine that these days was joined by physics and quantum chemistry. How we age, what diseases we will get, and how long we will live - all this is determined by our genes. Chromosomes are tightly packed DNA structures that carry our genetic code, a kind of body construction plan. Normal human cells contain 46 chromosomes. Just as rivets on shoelaces prevent chromosomes’ ends from fraying, telomeres secure the ends of chromosomes as caps, so that their sequences do not get tangled. Back in the 1960s-70s, it became clear that telomeres gradually shorten during cell division, and when they reach their critical length, the cell stops dividing, ages, and dies. So, telomeres are a kind of cell division counter that determines a person’s biological age. In 2009, the Nobel Prize in Physiology or Medicine was awarded to E.H. Blackburn, C.W. Greider, and J.W. Szostak "for the discovery of how chromosomes are protected by telomeres ...". Actually, they solved a major problem in biology of how the chromosomes can be copied in a complete way during cell divisions and how they are protected against degradation. It was demonstrated that the solution is to be found in the caps of the chromosomes – the telomeres – and in an enzyme that forms them – telomerase: the long, thread-like DNA molecules that carry our genes are packed into chromosomes, capped by telomeres. The latter contain G(guanine)-rich repeat sequences that are capable to fold into four-stranded so-called G-quadruplexes or G4 structures. In this work we investi- gate the molecular basis of the telomere model of aging. Its key trait is the hydrogen (H-) bonding patterns of G-tetrads that serve a top of G-quadruplexes composing telomeres. We show that these patterns demonstrate a variety of bonding characters – from classic hydrogen bonds to so called ‘over-coordinated oxygen (OCO)’ bifurcated H-bonds that thus result in floppiness of G-tetrad structures. This work has implications for the functionality of G-quadruplexes and, in turn, for the quadruplex-based telomere model of aging.