Introduction to Structural Biology

Proteins are the key effectors of the cell. They act as atomic scale molecular machines that have evolved to perform diverse and complicated actions. This includes the machines that generate energy, motors that move objects inside the cell, and all the machinery needed to duplicate cells and build a complex human body. A typical protein has a size on the order of 10nm or around 8 orders of magnitude smaller than a human. That is a similar difference between the height of a person and the diameter of planet earth. It is fascinating to imagine how a process of random variation and natural selection led to the existence of these molecular machines capable of building life at scales so much larger than themselves.

For the purpose of the lectures on structural bioinformatics it is important to remind yourselves about the basics of amino-acids and protein structure. Proteins are built up of amino-acids linked in a chain, forming a backbone with different amino-acid side-chains depending on the protein sequence. The folding and function of each protein depends on the exact sequence of amino-acids with each amino-acid in the chain differing only on the chemical properties of the side chain (e.g. positively or negatively charged, more or less hydrophobic). Sequential amino-acids tend to adopt specific secondary structural elements (e.g. alpha helix, beta-sheet) and different combinations of these elements result in different overall shapes. Different proteins can come together to form larger assemblies - protein complexes - which can often achieve more complex tasks.

Proteins are highly dynamic and these motions are essential for their function. A useful way to think about this is to consider that a given protein can exist in different conformations, some more energetically favorable than others. Proteins can use energy stored in small-molecules like ATP to cycle through different conformations. The energy of different conformations is often linked with the folding of the protein and these ideas are often discussed as an energy landscape. Drug binding or mutations that cause disease often change the stability of specific protein conformations which can impact on the folding or function of the proteins.

The 3D structure of proteins and protein complexes is not only beautiful but critical for us to understand how proteins work, how to design drugs that can alter their function or to rationalize how mutations end up causing a disease.