(579a) Characterizing the Features of Protein-Protein Interfaces over Time Using Molecular Dynamics

Protein-protein interactions are essential to how proteins carry out their functions. They bind to one another with high specificity due to interactions between functional groups at their interface. Understanding the thermodynamic details that govern these interactions presents the opportunity to both alter existing interactions and design novel ones. Protein docking algorithms use a variety of methods of varying complexity and run times to predict how proteins interact with one another. Unfortunately, docking methods often predict a large sample space of possible complexes for a specific system and the false complexes are indistinguishable from the correct one. The process of identifying the correct complex from this space can be difficult. This can limit the utility of docking programs specifically and computational methods in general for systems that lack experimental details, a situation we encountered when trying to understand how a known scFv bound Interleukin-6 (IL-6).

Our goal is to use short molecular dynamics (MD) simulations to distinguish correctly predicted complexes from incorrect ones. Towards this end, we have used MD to characterize the features of 20 experimentally determined protein-protein binding complexes. Each of the 20 complexes was analyzed using three separate five nanosecond MD simulations in NAMD. Subsequently, interface properties including buried surface area, calculated binding energy, shape complementarity, and pairwise residue-residue energies were calculated using the Rosetta Suite. Finally, false poses for each complex identified through docking programs were analyzed in a similar manner. This presentation will describe our findings, including the typical features of real protein-protein interfaces and how those features differ in false poses.

This work is part of a larger project on designing biosensors for biomanufacturing applications. Biosensing represents a rapidly growing field with many industries poised to benefit from the characterization of biosensing principles and the development of novel techniques. The design of biosensors relies on intricate knowledge of the many parts that are necessary for them to function. Binding proteins can be adapted for use as the recognition element of a biosensor because of their natural detection capabilities. This workflow will help us understand the mechanics behind the interactions that we seek to utilize for the design of our protein recognition element.