This study investigates molecular association processes under different environments. Ligand-protein association provides the first and critical step for most of the biological processes. The environment may affect molecular association in biological systems, such as the presence of biomolecular crowders or flow. However, the settings of experiments and modelling work for obtaining association rate constants may not be identical, which can be different from a biological environment as well. Commonly used experimental techniques such as isothermal titration calorimetry (ITC), surface plasmon resonance (SPR), and NMR spectroscopy measure ligand-protein association and/or their affinity. However, it is challenging to perform experiments in cellular environment, and the atomistic details during the encounter processes are not available experimentally. Using ligand xk263 binding HIV protease as a model system, we model atomistic detailed ligand-protein association using Brownian Dynamics simulations. We present the scenario of systems without flow of ligand diffusion to model systems similar to static cellular environment, along with the systems having flow to relate with the experimental SPR conditions. The association time was calculated under the influence of flow rate of ligands, presence of sensor surface, and the height of protein from the surface. The sensor surface is a self-assembled monolayer with CH<sub>3</sub> terminal group which provide a hydrophobic environment. In the presence of flow, the ligands diffuse rapidly in the system and associate faster, but the association probability decreases. However, on placing receptor 20Å above, the association probability increases as compared to the receptor placed at the bottom. This work brings the insight of ligand-protein association depending on various experimental SPR factors and provides a better picture of association- in comparison with different modelling and experimental conditions.

Study of flow and surface influence in ligand-protein association using molecular mechanics

ACS Spring Meeting 2021

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