Rob Coalson of the University of Pittsburgh is supported by the Chemical Theory, Models and Computational Methods program in the Chemistry Division for computational and theoretical studies of biological ion channels and nanopores. The Cellular Dynamics and Function Program in the Division of Molecular and Cellular Biosciences contributes to the award. The cell uses membranes composed of lipid bilayers to compartmentalize its contents. Specialized proteins insert into the membrane and allow transport through it as required for physiological function. For the cell membrane, the relevant membrane- bound proteins are called ion channels. They selectively pass ions through the membrane and are essential for nerve signal propagation, muscle contraction, auto-regulation of cell volume and production of biochemicals like insulin. The large Nuclear Pore Complex (NPC) plays a similar role in regulating the flow of molecular material into and out of the nucleus of eukaryotic cells. Residing in the nuclear membrane, NPCs controlthe flow of large biomolecules including proteins and RNAs between the cell nucleus and its cytoplasm. The work to be undertaken here entails large-scale computer simulations of the flow of material through these biological nanopores, using an appropriate level of atomic resolution, focusing on the molecular mechanisms that control these transport phenomena. It has importance for fundamental molecular biology, and ultimately may have relevance to medicine, as serious diseases are associated with improper function of ion channels and NPCs.
When a protein channel spanning a bilayer membrane is in its open state (i.e., is characterized by an appropriate aqueous pore), ions are driven through itby an electrochemical gradient which arises either from a concentration or an electrical potential difference across the membrane. Channel gating is a more complex process. Most gates operate on a time scale of milliseconds to seconds, too long to be simulated via brute force all atom Molecular Dynamics simulation. Understanding these processes requires the development of novel scale-spanning computational techniques. Another intriguing class of biological nanopores is comprised of large protein complexes which span the nuclear envelope in eukaryotic cells. The size and complexity of these Nuclear Pore Complexes (NPCs) present major challenges to molecular modeling analysis. The work to be performed on ion channel modeling will employ a novel divide and conquer multi-scale modeling approach. Molecular level detail extracted from relatively short all-atom Molecular Dynamics simulations will be fed into coarse-grained kinetic models. In addition to calculating ion permeation through realistic 3D models of channel proteins, problems involving mechanisms of ion channel gating and the coupling between permeation and gating will be tackled. The work on NPCs entails development of physico-chemically grounded coarse-grained simulation models combined with statistical mechanical analysis. These tools will enable study of larger systems and longer time scales than can be accessed by atomistic Molecular Dynamics simulations, namely, mesoscopic scales where collective behavior of many large molecules impacts the pore's ability to select molecular cargos to pass through it.