Molecular dynamics studies of K+ and Na+ channels and biomembranes based on a polarizable force field

Project Summary My group seeks to understand, at a fundamental level, the function of voltage-gated potassium (Kv) and sodium (Nav) channels using molecular dynamics (MD) simulations based on atomic models. Despite the enormous progress in structure determination, our comprehension of ion permeation, selectivity, activation, inactivation and

regulation remains incomplete. It is also crucial to keep in mind that a biological membrane is much more than a simple passive and featureless environment, but a complex dynamical molecular supra-assembly. The activity of ion channels is affected by a hosts of factors associated with the membrane, often modulated by ion-mediated

electrostatic interactions. Lipids are also directly involved in the activation of specific channels and signaling. MD simulations based on atomic models can play an important role in understanding the fundamental physical forces driving the structure and dynamics of these complex biomolecular systems. Using MD, we will study mechanism

of selective ion permeation (knock-on v.s. hard-knock) and the molecular basis of voltage-activation as well as C-type inactivation. The latter will examine the classic inactivating W434F Shaker K+ channel mutant based on recent structural information from cryo-EM and X-ray crystallography. On the experimental side, we continue to

investigate the factors affecting the activation and inactivation of K+ channels using cryo-EM and X-ray crystallography. We will also expand the scope of our research by examining the function of Nav channels, including selectivity, permeation, activation, and inactivation. To obtain meaningful computational results from MD simulations, it is crucial to accurately model the

physical forces associated with changes in the electronic distribution, a need that has stimulated the development of polarizable models going back many decades. Our efforts have focused on developing a polarizable force field (FF) in the context of the classical Drude oscillator model. The Drude model covers many

molecular components and has been implemented in many simulation programs (CHARMM, NAMD, GROMACS, OPENMM, and the CHEMSHELL QM/MM software). However, there is a critical need to expand the type of phospholipids covered to enable the modeling of a broader range of biomembrane processes. We will develop

the FF for the most important charged lipids like phosphatidylserine (PS) and phosphatidylglycerol (PG), and explore the biology of phosphatidylinositol-4,5-bisphosphate (PIP2). Calculations of the permeability coefficient of small molecules will be used to validate the optimized FF. We will also undertake several technical

developments on the propagation of the Drude model, enhanced sampling, conformational sampling, and machine learning algorithms, etc. The planned simulation studies based on an accurate and computationally efficient polarizable FF promise new fundamental insight into the function of ion channels and a host of

biomembrane phenomena. 1