This is one of those stories in science that is a little difficult to visualize. Let’s start with the shape of a DNA chromosome – a double helix, right? It looks a bit like a spiral staircase, with the rails being nucleotides and the steps being the bases. Now imagine descending a spiral staircase looking for a specific step on which to stop. As it turns out, that’s what DNA replicating proteins do. They literally slide up and down the ‘grooves’ between the nucleotide rails until they reach a place where the chemical configuration (molecular chemistry and shape) find exactly the right bases.
Until recently scientists didn’t know for sure that’s how proteins found their DNA. There were other models, for example, one that supposed the protein moved down the outside of a DNA strand in a more or less straight line. Some rather clever research (clever in this case meaning finding indirect evidence) by a team of scientists from the U.S. and India has provided the confirmation of the spiral model.
With a special fluorescence microscope, collaborating scientists led by Sunney Xie at Harvard University observed single protein molecules labeled with a fluorescent dye binding to and then sliding along the DNA. Although they could not see the exact path the molecules were sliding on, they could measure how fast the molecules were going.
Depending on how a protein moves along a DNA axis — either in a linear or helical pattern —it will encounter different degrees of resistance, as shown in the earlier paper. If protein motion is linear, its speed will decrease proportionately as its radius increases. If a protein exhibits helical motion, it will experience additional friction and its speed will decrease much faster as its radius increases.
Using a human DNA repair protein as a test for the protein rotation model, Paul Blainey, now at Stanford University, found the latter case to be true. When he increased the size of the protein, the rate of motion decreased much more rapidly than it would have for a simple linear motion.
Relying on the same technique, the group went on to analyze the diffusion rates of eight different proteins of various sizes. These molecules had highly diverse functions — such as DNA replication, cleavage, and repair — and DNA-binding mechanisms. They were also taken from a range of organisms, including mammals, bacteria, and human viruses.
The researchers observed the same pattern: The speed of each protein decreased dramatically as its radius increased, as predicted by the theory for helical sliding.
[Source: Brookhaven National Laboratory]
There are two grooves in a DNA strand, a major (22 Ångstroms wide) and a minor (12 Ångstroms wide). Most proteins (typically, transcription proteins) move along the major groove because it provides more contact surface with the bases. This is a kind of guided search mechanism that makes it possible for proteins to do their work much faster than might be expected if they just freely floated around the cell and only occasionally contacted the DNA strands.
This is one of those nitty-gritty pieces of science. It’s the inner workings kind of stuff that might not seem terribly relevant to the big picture. In a way, that’s true. But if we’re ever going to get a practical handle on how our genetic machinery works – and therefore how life works – this is where it’s at. Knowing that replication proteins slide down the helix grooves not only explains how the complex matching of molecular configuration works, but it may also make it possible to manipulate it. What if, for example, we could stop the spread of a viral infection by preventing its replication proteins from efficiently finding the right ‘step’ in the DNA strand?