Structure-based drug design is an important tool, and many pharmaceuticals are designed to target specific proteins in the body. However, most protein studies (in vitro) are conducted in dilute conditions (salt-buffer solutions), which poorly mimic the environment that proteins normally operate in, living cells. The inside of a cell is crowded, packed with biomolecules of various shapes and sizes which could confine and change the structure and dynamics of proteins. However, the precise mechanism by which the crowding and confinement impacts a protein’s structure and function differ with the macromolecular crowder. One of the methods to study these effects is to employ synthetic crowders to see how they impact a protein’s structure, shape, and function. In the present study, a fusion of experimental and computational methods, namely, Atomic Force Microscopy (AFM) and Molecular Dynamics (MD) simulations, have been used to explore the impacts of molecular crowding. By placing a protein solution treated with a macromolecular crowder on an atomically flat piece of highly ordered pyrolytic graphite (HOPG), the study with AFM offered a topographical representation of the sample. In addition, using coarse-grained MD simulations, protein molecules have been simulated in crowded environments offering us an effective way of analyzing the effects of macromolecular crowding on single protein systems. The presentation will showcase some of the preliminary results of this study. By analyzing the results from these experimental and computational systems, we hope to be able to gain valuable insight into how proteins operate in their natural environments and apply these data to improve protein-based drug design and distribution.

Exploring the effects of macromolecular crowding on protein systems: A combined experimental-computational approach

ACS Spring 2022

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