Past Research Highlights

Immature HIV-1 lattice assembly dynamics are regulated by scaffolding from nucleic acid and the plasma membrane 

In this work, we use coarse-grained molecular models to simulate the early stages of viral assembly, packaging, and budding during HIV-1 replication. In collaboration with the Lippincott-Schwartz Group at the NIH and HHMI, we provide a molecular-level view into the dynamics of this process and show that Gag polyproteins engage with viral RNA and deformations along the cell membrane to both instigate and control its self-assembly into the immature HIV-1 lattice. We further demonstrate the importance of specific features of the modeled Gag domains. Taken together, our findings elucidate a simple regulatory network of interactions that may contain viable targets for antivirals.

Coarse-grained Directed Simulation

In this work, we show that using minimal bias methods, we can simulate a protein in solution and have it behave as if embedded in a different environment, such as a large protein complex. This is done by learning a bias on coarse-grained observables, such as distances or angles between beads representing large collections of atoms in the protein. The bias is targeted such that these observables sample the correct mean and variance from simulations in the whole complex. We apply this to the protein actin in solution, and discuss how this would be useful for future expensive sampling or QM/MM simulations performed on actin, previously done with rigid constraints that pollute the protein's dynamics. 

Improved Ab Initio Molecular Dynamics by Minimally Biasing with Experimental Data 

In this work, we apply the Experiment Directed Simulation (EDS) method to improve the properties of water simulated with Ab Initio Molecular Dynamics (AIMD) simulations at a poor/cheap DFT level of theory. A simple classical bias is learned on-the-fly from the O-O radial distribution function, which causes the AIMD water to match much better the structural properties of water seen in experiment, including diffusion. Applying this bias to a hydrated excess proton in water also significantly improves the properties of that system, without the need for learning a new bias potential.  

Development of Reactive Force Fields Using Ab Initio Molecular Dynamics Simulation Minimally Biased to Experimental Data

By using relative entropy minimization (REM) and minimally biased ab initio molecular dynamics (AIMD) simulations, we have developed two new multiscale reactive molecular dynamics force fields for a hydrated excess proton. We show that both of these models closely reproduce the solvation structure of the reference AIMD data, and we also demonstrate the capabilities of REM to develop reactive force-fields.

Extending the Range and Physical Accuracy of Coarse-grained Models: Order Parameter Dependent Interactions

The choice of basis function is an important decision that must go into the construction of a coarse-grained model. Coarse-grained models are usually built using a basis set of pairwise interactions for non-bonded interactions and expanding into 3-body and on to expand the basis set. This paper introduces the use of order parameters, particularly local density and absolute position, as an efficient alternative to expand basis sets. The order parameter basis set allows for a drastically improved description of liquid-vapor interfaces in coarse-grained methanol.

Highly Coarse-Grained Representations of Transmembrane Proteins

Internal symmetry in transmembrane protein — exact or approximate — is common and it has consequences for the Gaussian fluctuations around the equilibrium structure of the proteins. We substantiate that a coarse-grained mapping must preserve the underlying structural symmetries (both structural symmetry groups and modular repeats in the secondary structure, depending on the resolution) and show that this can be used as a design principle to construct coarse-grained mappings. 

The Origin of Coupled Chloride and Proton Transport in a Cl–/H+Antiporter

ClC-ec1, a Cl- /H+ antiporter, is critical for maintaining ion concentrations and PH gradients in bacteria in acidic environments. In this work, we computationally characterized the rate-limiting step of the overall proton transport process in ClC-ec1 and the essential mechanism of the Cl-/H+ coupling. We found that the highest barrier for PT is located at the deprotonation of E148, and this barrier is significantly reduced by the binding of Cl- in the central site, which displaces E148 and thereby facilitates its deprotonation.

Molecular Modeling and Assignment of IR Spectra of the Hydrated Excess Proton in Isotopically Dilute Water

We developed a mixed quantum-classical model for the vibrational spectroscopy of the excess proton in isotopically dilute water.  The model is useful for decomposing IR spectra into contributions from different aqueous proton configurations as validated by our experimental collaborator Andrei Tokmakoff (UChicago). We find that the shift from Eigen to Zundel-like configurations is distinguished by a decrease in the O—H transition frequency.

Acid Activation Mechanism of the Influenza A M2 Proton Channel

The influenza A M2 channel (AM2) transports protons into the influenza virus upon acid activation. MS-RMD simulations were performed to characterize the free energy profiles of the proton transport events in the M2 channel. Our results show that decreasing pH causes the Trp41 gate to open, which decreases the deprotonation barrier of the His37 tetrad. This leads to channel activation, which is characterized by increased proton conductance.

Transition-Tempered Metadynamics is a Promising Tool for Studying the Permeation of Drug-like Molecules through Membranes

The recently developed transition-tempered metadynamics (TTMetaD) has been proven to converge asymptotically without sacrificing exploration of the collective variable space in the early stages of simulations. We applied TTMetaD to study the permeation of drug-like molecules through a lipid bilayer to investigate its usefulness in medicinal chemistry. Compared to other enhanced sampling methods, TTMetaD is able to predict the most accurate and reliable estimate of the potential of mean force in the early stages of the simulations. We also show that using multiple randomly initialized replicas allows convergence analysis and provides an efficient means to converge the simulations in shorter wall times and CPU times

Fascin and α-Actinin-bundled Networks Contain Intrinsic Structural Features That Drive Protein Sorting

Actin-binding protein sorting is critical for the self-organization of diverse dynamic actin cytoskeleton networks within a common cytoplasm. In this work it was shown using in vitro reconstitution techniques including biomimetic assays and single-molecule multi-color total internal reflection fluorescence microscopy, that the sorting of the prominent actin-bundling proteins fascin and α-actinin mutually exclude each other by promoting their own recruitment and inhibiting recruitment of the other, resulting in the formation of distinct domains. We designed a lattice model which allows us to predict the energetic barrier for switching from one domain to another by comparison of the model results to experimental domain sizes. 

On the Representability Problem and the Physical Meaning of Coarse-Grained Models

We discuss the relationship between coarse-grained (CG) observables and the corresponding fine-grained (FG) or experimental observables in the framework of systematic bottom-up CG modeling. The importance of this issue is illustrated with a simple polymer system that has implications for the coarse-graining of intramolecular degrees of freedom.

Multiscale Simulations of Protein Facilitated Membrane Remodeling

Many crucial biological processes, such as cell division, protein trafficking, and cell signaling, involve large-scale membrane shape and topology changes that are facilitated by complex membrane-protein interactions. In this Review we discuss the recent advances of our group in multiscale computational approaches for studying protein-mediated large-scale membrane remodeling.

Multiscale Simulations Reveal Key Features of the Proton Pumping Mechanism in Cytochrome c Oxidase

We used MS-RMD simulations to characterize the free energy profiles of the proton transport events in the cytochrome c oxidase (CcO) that enable proton pumping and chemical reaction. Our results show that the transfer of both the pumped and chemical protons are thermodynamically driven by electron transfer, and explain how proton back leakage is avoided by kinetic gating. 

Cations Stiffen Actin Filaments by Adhering a Key Structural Element to Adjacent Subunits

In this work, we use molecular dynamics simulations and coares-grained techniques to study actin filaments which have incorporated magnesium ions into recently predicted binding sites between actin subunits. Binding of a magnesium ion into a predicted "stiffness site" adheres the actin DNase-binding loop (D-loop) to its long-axis neighbor, which increases the filament torsional stiffness and bending persistence length. Our analysis shows that bound D-loops occupy a smaller region of accessible conformational space and that cation occupancy buries key conserved residues of the D-loop, restricting accessibility to regulatory proteins and enzymes that target these amino acids.