Computational membrane biophysics: From ion channel interactions with drugs to cellular function

Abstract

The rapid development of experimental and computational techniques has changed fundamentally our understanding of cellular-membrane transport. The advent of powerful computers and refined force-fields for proteins, ions, and lipids has expanded the applicability of Molecular Dynamics (MD) simulations. A myriad of cellular responses is modulated through the binding of endogenous and exogenous ligands (e.g. neurotransmitters and drugs, respectively) to ion channels. Deciphering the thermodynamics and kinetics of the ligand binding processes to these membrane proteins is at the heart of modern drug development. The ever-increasing computational power has already provided insightful data on the thermodynamics and kinetics of drug-target interactions, free energies of solvation, and partitioning into lipid bilayers for drugs. This review aims to provide a brief summary about modeling approaches to map out crucial binding pathways with intermediate conformations and free-energy surfaces for drug-ion channel binding mechanisms that are responsible for multiple effects on cellular functions. We will discuss post-processing analysis of simulation-generated data, which are then transformed to kinetic models to better understand the molecular underpinning of the experimental observables under the influence of drugs or mutations in ion channels. This review highlights crucial mathematical frameworks and perspectives on bridging different well-established computational techniques to connect the dynamics and timescales from all-atom MD and free energy simulations of ion channels to the physiology of action potentials in cellular models.

Biophysical Psychiatry—How Computational Neuroscience Can Help to Understand the Complex Mechanisms of Mental Disorders

“…This can help in identifying risk-conferring SNPs and discovering the correlation structure between the SNPs, both locally and across the genome, and thus complements the GWAS data from large consortia. Second, quantitative data on ion-channel behavior and the contributions of different subunits and other proteins are rapidly growing, thanks to both online databases (such as Channelpedia and ICGenealogy) and new insights from molecular dynamics simulation approaches (111). Third, new large-scale projects such as the Allen Brain Atlas () and Human Protein Atlas () offer unique, standardized data sets on the expression of genes in both mice and men.…”

Mechanistic Understanding from Molecular Dynamics in Pharmaceutical Research 2: Lipid Membrane in Drug Design

“…Finally, there are cases where the mode of action of the drug does not even involve interaction with a protein; the drug acts directly on a specific biomembrane rather than with a protein. In all of these cases, MD simulation, a mature tool for the study of biomembranes [19][20][21][22][23][24][25][26][27], can provide a window on the role the lipid membrane plays in drug action; this review paper describes how MD provides mechanistic insight and includes many examples where it has been successfully applied. We will first discuss the behavior of drug molecules in the membrane, then how drugs transfect through membranes that form biological barriers and how drugs can, collectively, at sufficient concentration, affect the properties of the membrane.…”

Atomistic modeling towards predictive cardiotoxicity

“…Significantly, a structure of the hERG channel in a putative open state was recently determined at a 3.8 Å resolution by cryo-EM (23) and was used in this study. The advances in molecular modeling and simulation methodology (24) and availability of powerful and efficient high-performance computing resources (25,26) have made rigorous atomic-resolution investigation of ion channel function (27), and ion channel -drug interactions (28) now feasible .…”