Proteins and the Computational Microscope
The computational microscope is a set of theoretical and numerical tools which allows us to interpret and extend experimental data
Virtually all processes that are essential for life such as, photosynthesis, respiration, cell signaling, and energy production/storage are carried out by biological molecules we call proteins. Imagine if you had a microscope powerful enough to resolve individual atoms of a protein molecule. What would you see? You would see thousands of atoms linked together as amino acid peptide units creating a polypeptide chain. The chain often has a well defined three dimensional structure as reflected in the structure of a DNA synthesizing protein (Fig (a)). Sometimes different protein units can team up together to form larger complexes to carry out a specific task. For example, the rhodopsin-transducin complex located at cell boundaries (Fig (b)) gets activated by light to initiate a signaling process within the cells of the eye which ultimately leads to vision.
What if our microscope allowed us to monitor atomic motions? What would we see? In their solvent environment and ambient conditions, proteins exhibit thermal motions over timescales ranging from femtoseconds (10-15 seconds) to hours (103 seconds). That's a whopping 18 orders of magnitude! Motion at the fastest timescales occurs over very small distances, involving the stretching of bonds between two atoms. Motion at the larger timescales involves larger and larger groups of atoms, who tend to act in unison. Fig (c) lists some examples of thermal motions in protein molecules along with their corresponding timescales, as observed from NMR/optical spectroscopy experiments and computational studies.
The structure and associated thermal motions of proteins are both intimately connected to their function. Experimental studies and theoretical models have been able to establish some ground rules to connect protein structure and function. For instance, the shape of a protein and the electric charge carried by groups of atoms on the protein surface can reveal the types of molecules the protein can bind. Chemical reactions carried out by proteins often occur at special active sites inside the protein. On the other hand, connecting the thermal motions of proteins to their associated function has proven to be a formidable challenge. Why? First, no single experimental or computational method can probe the entire temporal range of thermal motions. Second, it is an open challenge to separate out thermal motions and assign the contributions on different timescales to a particular molecular process. Third, the problem lies at the interface of physics, chemistry, and molecular biology requiring an interdisciplinary toolset as well as mindset.
We address the fascinating question of how thermal motions drive various protein functions such as catalysis, molecular recognition, cell signaling, and electron transfer. We also build theoretical models to describe processes such as electron transfer and optical excitation energy dynamics within the protein structures. The challenging problem of visualizing protein dynamics on different timescales is being tackled using high performance computational modeling and simulations of proteins under experimental/physiological conditions. In such calculations protein structure is described at varied resolutions ranging from single atoms to entire protein domains. The motion of protein atoms, which is driven by thermal energy, is described classically when no chemical transformations (e.g breaking or forming of covalent bonds) occur. Dynamics with chemical transformations are modeled using a mixed scheme, wherein the atoms participating in the reactions obey the laws of quantum mechanics, and the rest of the protein/solvent atoms obey the laws of classical mechanics.