Several diverse projects are being pursued. These are the major ones pursued during the past year. Amyloid-βoligomers interacting with lipid bilayers. This project is focused on all-atom molecular dynamics simulations of the interaction between the amyloid-β(Aβ) peptide and lipid membranes. Interest in Aβstems from the connection between the misfolding and aggregation of this peptide and Alzheimer's disease. When studying proteins anchored or inserted into lipid membranes, as observed in the case of Aβ, one of the technical and theoretical problems with this kind of simulations involves the limitations of periodic boundary conditions (PBC). The area/lipid in the two leaflets becomes uneven and the relative number of lipids in the two leaflets of a bilayer should be readjusted during a simulation. Applying the P21 boundary conditions to the protein-lipid systems, which allow the transition of lipids between the two leaflets, enables the simulation of larger bilayers. CHARMM is the only simulation package that permits this lipid behavior. The study brings more insight into the structure and dynamics of the amyloid fibrils in the proximity of lipid membranes, as well as helps elucidate the mechanism of interaction between the two entities. This could have possible implications in both diagnosis and treatment of the disease. Computational study of an ion channel. Hyperpolarization-activated cyclic nucleotide-gated 2 (HCN2) ion channels are expressed in the sinoatrial node, dorsal root ganglia and the basal ganglia. They play fundamental roles in electric signaling in nerve, muscle and synapse, but their function and gating mechanism are not completely understood. The overall goal of the project is to gain insight into the mechanism of the HCN2 channel activation upon binding of cyclic adenosine monophosphate (cAMP) to its intracellular C-terminal. Many mechanisms have been proposed for the opening motion propagation in the channel, but they do not completely explain the entire channel behavior. A novel theory states that upon cAMP binding, a part of the HCN2 C-terminal, called the C-helix, stabilizes its secondary structure and moves towards the binding pocket to make contacts with cAMP. Its movement is correlated with the opening conformational change of the channel pore. This theory is being tested using a novel computational method, the self-guided Langevin dynamics (SGLD), which employs guided forces to enhance the low-frequency motion and accelerate the protein conformational search. Starting from the holo state structure and using the distances from tmFRET measurements as restraints, the protein is guided into its apo state. The simulations enable sampling of conformations along this transition, giving insight into the occurring structural changes and ultimately into the HCN2 gating mechanism. Molecular dynamics and constant pH simulations of internal ion-pairs. Internal ion-pairs are at the core of many biochemical processes such as ion and water homeostasis, enzymatic catalysis, and proton and electron transfer reactions in bioenergetics proteins. To understand the functionally important ion-pairs, it is necessary to know the pKa values of ionizable groups in the ion-pair, as well as to characterize the structural change that is coupled to protonation/deprotonation processes. We are studying the V23E-L36K and V23K-L36E variants of staphylococcal nuclease as model systems for understanding of internal ion-pairs. The two ion-pairs have been extensively experimentally characterized by our collaborator Prof. B. Garcia-Moreno at the Johns Hopkins University. Through explicit solvent MD simulations of ion pairs in four different protonation states we are characterizing the structures of each ionization state, and through constant pH simulations were are calculating the pKa values of ionizable groups in the pairs. Computational study of nitrogen oxides. Nitric oxide (NO) is one of the simplest biological molecules in nature, but also in nearly every phase of biology and medicine with its role ranging from a critical endogenous regulator to blood flow, a principal neurotransmitter, to major pathophysiological mediator of inflammation and host defense. We continue our collaboration with Dr. David Wink from NCI to apply electronic structure calculation of NO and its sequential reactions in aqueous solution. We are applying relatively low cost spin flip density functional theory (SP-DFT) on NO and relative reactive nitrogen species (RNS) to obtain results comparable to very high level of multireference quantum chemistry theories. Calcium ATPase Conformational Transition through Self-Guided Langevin Dynamics Simulation. The sarcoplasmic reticulum (SR) Ca2+-ATPase (SERCA1a) transport calcium ions from cytoplasm into the reticulum and relaxes the muscle cells. Many crystal structures of SERCA1 in various binding states have been determined, which provide insights into the mechanism of transport Ca2+ across the membrane. To understand the transport mechanism, it is desirable to study the dynamic process during the conformation transition. Self-guided Langevin dynamics (SGLD) is a simulation method capable of studying events with large conformational change. SGLD simulations of SERCA at different binding states produce conformational transitions between conformational states. New conformations for E1.2Ca2+ and E2.P state have been identified and at E2 state the crystal structure is a preferred conformation. Mechanistic Aspects of Acid Catalyzed Homogeneous Reduction of Dioxygen with Bifunctional Catalysts. The transfer hydrogenation catalyst, Cp*IrH(TsDPEN) (where TsDPEN is H2NCHPhCHPhN(SO2C6H4)−), 1H(H), can be used for the catalytic reduction of O2. Theoretical calculations on transfer hydrogenation catalysts have been somewhat limited. In this project we are investigating the mechanism of the reaction of Cp*IrH(TsDPEN) with O2 in acidic conditions, through theoretical structural calculations. This work plans to examine the effect of acid on the catalytic production of water with Cp*IrH(TsDPEN) from H2 and O2 using by density functional theory (DFT). Also, we will compare the energetics of the process with respect the analogous pathways in neutral conditions. Our results show that the O2 reduction proceeds by intermediate production of H2O2, which reacts with the 18e amino-hydride Cp*IrH(TsDPEN) (1H(H)) to eliminate water, restore CpIr(TsDPEN)+ (1H+), and restart the catalytic cycle. The outcomes of our computations show that the elimination of water occurs in one step because of the simultaneous transfer to the oxygen atoms of the peroxide of the proton from the acid and the hydride from the metal. The energetics of the calculated pathways appears to be drastically more favorable than the analogous pathways in neutral conditions (PES1). Delivery of MicroRNA-29 family based cylindrical nucleic acid multifunctional nanoparticle conjugates for Lung Cancer. Efficient delivery of miRNA for therapeutic purposes is extremely challenging. The delivered miRNA needs to be routed to the target organ, enter the cell, and reach the intracellular target in its active form. Chemical modifications and nanoparticle delivery systems have been developed to overcome these challenges. The specific goals of this project is threefold: First we will investigatethe interaction between miRNA-AuNPs and multifunctional nanoparticles. Second, using high miRNA-29 family surface coverage we will try to understand the concentrations of miRNA-multifunctional nanoparticles needed for a high-efficiency knockdown and temperature dependence. Third, using coarse-grained molecular dynamic simulations we will explore the permeation characteri familytics of ligand-coated nanoparticles through a model membrane.
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