Multiscale Computer Modeling to Evaluate Protein-Ligand Off-Target Interactions

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To be biologically active, all proteins and small molecules must physically fit into the binding site(s) within their targets. However, in reaching their targets, they have to interact with a variety of cellular components. All these events increase the probability for a molecule, particularly a small molecule of exogenous cellular origin (e.g. food additives and pollutants), to bind to an undesired off-target(s), leading to the disruption of several physiological functions. My research program is focused on using computer simulations to understand the biophysical mechanisms behind off-target interactions of proteins and small molecules. We use cardiac ion channels as a model to study this process. Cardiac ion channels (e.g. hERG) are membrane proteins that contain promiscuous binding sites and have been reported to interact with diverse small molecules. More importantly, these interactions' data are publicly available and have been maintained over the last decades, making cardiac ion channels an excellent model to understand proteins' off-target interactions using computer simulations. Over the last few years my research group and others developed various computer-based models for several cardiac channels. Although, these models provided useful tools to understand the mechanisms of ions' passage and off-target interactions through their pore domains, there are still many research questions that need to be answered. For example, emerging evidences emphasize the inhibition of channel trafficking as an alternative off-target pathway for small molecules to reduce cardiac channels' density, hence, lowering ions' flow. They mainly do that by blocking the interactions of ion channels with their molecular chaperones (e.g. HSP70/90), which significantly reduces the number of active channels in the membrane. In addition, interactions of cardiac channels with certain lipids or sex hormones can also modulate their activity. The off-target mechanisms for small molecules to exploit these lipid-mediated sites/pathways are not fully understood. Thusly motivated, the current proposal expands upon our earlier work and aims to understand the off-target mechanisms by which small molecules inhibit cardiac channels' trafficking and interact with lipids' binding sites in these channels from a computational perspective. Long-term goal: To understand the biophysical mechanisms behind off-target interactions of proteins and small molecules. Short-term goals: We will use multiscale simulations to: 1) Study the effects of small molecules on inhibiting channels-chaperones formation. 2) Study the effects of lipid-soluble molecules on cardiac ion channels' modulation. Significance: The successful implementation of this proposal can help overcome a major limitation of current off-target computer-based predictive models, which mainly focused on channels' pore blockade. This proposal is also expected to train a significant number of HQPs.