Developing and applying new theoretical and computational methods to study complex condensed phase systems
Attempts to coarse-grain the actin filament at the resolution of tens to hundreds of residues per bead are stymied by the presence of long-lived metastable heterogenous fine structure, such as the folding state of the D-loop of subdomain 2 and ATP/ADP binding state, within the beads. Dama et al. present a new general systematic methodology for coarse-graining biomolecules at utralow resolution that bridges particle-based and Markov-state based modeling to allow for dynamics both of and within coarse-grained beads.
Unraveling the Role of the Protein Environment for [FeFe]-Hydrogenase: A New Application of Coarse-Graining
[FeFe]-hydrogenase is an enzyme that catalyzes the hydrogen formation reaction. Electron and proton transport in this enzyme were investigated using a novel combination of coarse-graining and Marcus theory that revealed activation of a previously unknown proton transport channel during electron transport.
Molecular Dynamics Simulations of Proton Transport in 3M and Nafion Perfluorosulfonic Acid Membranes
Proton transfer in the 3M membrane and Nafion is studied and compared using multistate reactive molecular dynamics simulations. The Grotthuss mechanism of proton transport is shown not to be the cause in the conductivity difference as previously conjectured.
A recently developed method to model the total energy of a solute-solvent system as a sum of local interactions was generalized, extending its use to the modeling of reactive systems within a multiconfigurational scheme. At the air-water and hydrophobic wall-water interfaces, it was observed that the energetic penalty due to the loss of coordinating water molecules as the excess proton approaches the interface is more than compensated with the displacement of unfavorable interfacial water molecules. Examination of damped fluctuations of the instantaneous air-water interface in the vicinity of the excess proton further eluded to an entropic penalty.
Using all-atom molecular dynamics and coarse-grain simulation methods, we have studied the interactions of myosin II with an actin filament in order to understand how each protein influences the dynamics of the other. We observed that the actin-binding "jaws" of myosin are more strongly closed when bound to actin than when free from actin, and that the torsional rigidity of the actin filament increases when bound to myosin compared to myosin-free actin filaments.
We used coarse-grained molecular simulations to investigate the way N-BAR proteins interact with one another on the surface of the membrane and generate its curvature. We show a striking assembly of proteins into linear aggregates and meshes that not only helps in understanding how subsequent membrane remodeling may occur, but demonstrates a mechanism for their very rapid recruitment, crucial for e.g. synaptic transmission.
By combining Fragment Molecular Orbital (FMO) theory and Multi-state Reactive Molecular Dynamics (MS-RMD) theory, we develop a new approach to simulating chemical reactions using fragment-based electronic structure theory. Our new method, FMO-MS-RMD, offers a solution to the issues of dynamic fragmentation and non-unique fragmentation, which are often encountered in fragment-based calculations involving reactive molecules, such as protonated water systems.
The efficent use of very large-scale "ultra-coarse-grained" (UCG) molecular models presents significant difficulties to conventional molecular dynamics software. The Voth group combined and developed a number of unorthodox algorithms to produce a highly scalable and memory efficient molecular dynamics program, designed from first principles for UCG models: UCG-MD.
Single-Molecule Studies Reveal a Hidden Key Step in the Activation Mechanism of Membrane-Bound Protein Kinase C-α
We have employed atomistic MD simulations to reveal the membrane-docking geometries of the regulatory C1 domains, providing valuable information to assist single-molecule experiments to reveal the hidden steps of Protein Kinase Cα (PKCα) activation. This work represents the first study to combine simulations and experiments to investigate PKCα C1 domains in membrane-bound environments.