The fine art of preparing membrane transport proteins for biomolecular simulations: Concepts and practical considerations

• Published in: Methods (San Diego, Calif.) Calif.), 2021-01, Vol.185, p.3-14
• Main Authors: Shiref, Hana, Bergman, Shana, Clivio, Sophie, Sahai, Michelle A.
• Format: Article
• Language: English
• Subjects: Algorithms; Computational modelling; Dopamine Plasma Membrane Transport Proteins - metabolism; Drug Discovery; Humans; Ligands; Membrane protein simulations; Membrane Transport Proteins - chemistry; Membrane Transport Proteins - metabolism; Molecular docking; Molecular dynamics; Molecular Dynamics Simulation; Protein Binding; Protein structure preparation; Small molecule parameterization
• ISSN: 1046-2023; 1095-9130
• DOI: 10.1016/j.ymeth.2020.02.009

•Concepts and methodologies for the initial steps of a membrane protein setup.•Present the strengths and limitations of various software packages and tools for setup and analysis.•Highlight the open challenges faced by novices.•Workflow of the setup of a membrane transport protein, hDAT in complex with various stimulants. Molecular dynamics (MD) simulations have developed into an invaluable tool in bimolecular research, due to the capability of the method in capturing molecular events and structural transitions that describe the function as well as the physiochemical properties of biomolecular systems. Due to the progressive development of more efficient algorithms, expansion of the available computational resources, as well as the emergence of more advanced methodologies, the scope of computational studies has increased vastly over time. We now have access to a multitude of online databases, software packages, larger molecular systems and novel ligands due to the phenomenon of emerging novel psychoactive substances (NPS). With so many advances in the field, it is understandable that novices will no doubt find it challenging setting up a protein-ligand system even before they run their first MD simulation. These initial steps, such as homology modelling, ligand docking, parameterization, protein preparation and membrane setup have become a fundamental part of the drug discovery pipeline, and many areas of biomolecular sciences benefit from the applications provided by these technologies. However, there still remains no standard on their usage. Therefore, our aim within this review is to provide a clear overview of a variety of concepts and methodologies to consider, providing a workflow for a case study of a membrane transport protein, the full-length human dopamine transporter (hDAT) in complex with different stimulants, where MD simulations have recently been applied successfully.