Calculations of Absolute Free Energies, Enthalpies, and Entropies for Drug Binding.

Computer simulation methods can aid in the rational design of drugs aimed at a specific target, typically a protein. The affinity of a drug for its target is given by the free energy of binding. Binding can be further characterized by the enthalpy and entropy changes in the process.

Effects of polarizability and charge transfer on water dynamics and the underlying activation energies.

A large number of force fields have been proposed for describing the behavior of liquid water within classical atomistic simulations, particularly molecular dynamics. In the past two decades, models that incorporate molecular polarizability and even charge transfer have become more prevalent, in attempts to develop more accurate descriptions. These are frequently parameterized to reproduce the measured thermodynamics, phase behavior, and structure of water.

The pH Response of a Peptoid Oligomer.

Polypeptoids are -substituted glycine polymers, which differ from peptides in the placement of the side chain on the amide nitrogen rather than the C carbon. A peptoid with a chiral side chain containing both an aromatic group and carboxylic acid has a structure that responds to pH changes. All-atom molecular dynamics simulations using a force field specifically tuned for peptoids were carried out with an advanced sampling method for the peptoid ()--(1-carboxy-2-phenylethyl)glycine in the high and low pH limits.

Unraveling the Role of Charge Patterning in the Micellar Structure of Sequence-Defined Amphiphilic Peptoid Oligomers by Molecular Dynamics Simulations.

Electrostatic interactions play a significant role in regulating biological systems and have received increasing attention due to their usefulness in designing advanced stimulus-responsive materials. Polypeptoids are highly tunable N-substituted peptidomimetic polymers that lack backbone hydrogen bonding and chirality. Therefore, polypeptoids are suitable systems to study the effect of noncovalent interactions of substituents without complications of backbone intramolecular and intermolecular hydrogen bonding.

Simulation studies of polypeptoids using replica exchange with dynamical scaling and dihedral biasing.

Polypeptoids differ from polypeptides in that the amide bond can more frequently adopt both cis and trans conformations. The transition between the two conformations requires overcoming a large energy barrier, making it difficult for conventional molecular simulations to adequately visit the cis and trans structures. A replica-exchange method is presented that allows for easy rotations of the amide bond and also an efficient linking to a high temperature replica.

Molecular dynamics simulations of the flexibility and inhibition of SARS-CoV-2 NSP 13 helicase.

The helicase protein of the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) is both a good potential drug target and very flexible. The flexibility, and therefore its function, could be reduced through knowledge of these motions and identification of allosteric pockets. Using molecular dynamics simulations with enhanced sampling, we determined key modes of motion and sites on the protein that are at the interface between flexible domains of the proteins.

Molecular dynamics simulations of allosteric motions and competitive inhibition of the Zika virus helicase.

The 2015 Zika outbreak sparked major global concern and emphasized the reality and dangers still posed by mosquito borne pathogens. While efforts have been made to develop a vaccine and other therapeutics, there is still a great demand for antiviral drugs targeting Zika and other flaviviruses. The non-structural protein 3 (NS3) helicase is a vital component of the viral replication complex, tasked with unwinding the viral dsRNA molecule into single strands.

Channelrhodopsin C1C2: Photocycle kinetics and interactions near the central gate.

Channelrhodopsins (ChR) are light-sensitive cation channels used in optogenetics, a technique that applies light to control cells (e.g., neurons) that have been modified genetically to express those channels.

Insights into the Thermal Response of a Poly(ethylene oxide)-poly(propylene oxide)-poly(ethylene oxide) Triblock Polymer in Water.

A thermal responsive block copolymer made up of ethylene oxide (EO) and propylene oxide (PO) blocks was simulated with optimized atomistic potentials and enhanced sampling methods over a range of temperatures. The results for the L42 pluronic polymer (EO)(PO)(EO), which is known to undergo a transition in this temperature range, and the similarly sized (EO) polymer, which does not, are compared. The thermal responsive L42 polymers in a dilute solution tend to aggregate, and this tendency gets stronger as temperature increases.

An Implementation of Replica Exchange with Dynamical Scaling for Efficient Large-Scale Simulations.

An implementation of the replica exchange with dynamical scaling (REDS) method in the commonly used molecular dynamics program GROMACS is presented. REDS is a replica exchange method that requires fewer replicas than conventional replica exchange while still providing data over a range of temperatures and can be used in either constant volume or constant pressure ensembles. Details for running REDS simulations are given, and an application to the human islet amyloid polypeptide (hIAPP) 11-25 fragment shows that the model efficiently samples conformational space.

Analysis of Atomistic Potentials for Poly(ethylene glycol) Ethers.

Two different potentials, the modified TraPPE-UA model of Fischer, J. [ 2008, 112, 2388-2398] and the modified general AMBER force-field (GAFF) model of Barbosa, N. S.

Polarizable MD simulations of ionic liquids: How does additional charge transfer change the dynamics?

Both experimental and computational evidence exist that Coulomb interactions between the molecular ions in ionic liquids are significantly damped by almost a factor of two. This circumstance is often used to justify charge scaling. However, as polarizable MD simulations are also capable of explaining the reduced Coulomb interaction between the ionic liquid ions [C.

Coarse-Grained Models for Constant pH Simulations of Carboxylic Acids.

A model for carboxylic acids, in both the protonated and deprotonated states, is developed in which hydrogen interaction sites are not used and all interactions are short-ranged. A method for constant pH simulations, which exploits these features of the model, is developed. The constant pH method samples protonation states by making discrete Monte Carlo steps and is able to efficiently move between states in two steps.

Coarse-Grained Simulations of Aqueous Thermoresponsive Polyethers.

Thermoresponsive polymers can change structure or solubility as a function of temperature. Block co-polymers of polyethers have a response that depends on polymer molecular weight and co-polymer composition. A coarse-grained model for aqueous polyethers is developed and applied to polyethylene oxide and polyethylene oxide-polypropylene oxide-polyethylene oxide triblock co-polymers.

Water hydrogen degrees of freedom and the hydrophobic effect.

Hydrogen bonds are the key interaction that establishes the liquid and solvent properties of water. Nevertheless, it is possible to construct an accurate molecular model of water which does not include hydrogens or any orientational interactions. Using this model, we calculate the structural and thermodynamic properties for the hydration of methane and ethane.

Towards a coarse-grained model of the peptoid backbone: the case of N,N-dimethylacetamide.

In this study, a coarse-grained (CG) model for N,N-dimethylacetamide (DMA), which represents the polypeptoid backbone, is developed as a step towards establishing a CG model of the complex polypeptoid system. Polypeptoids or poly N-substituted glycines are a type of peptidomimetic polymers that are highly tunable, and hence an ideal model system to study self-assembly as a function of chemical groups in aqueous soft matter systems. The DMA CG model is parameterized to reproduce the structural properties of DMA liquid as well as a dilute aqueous solution of DMA using a reference all atom model, namely the OPLS-AA force-field.

The influence of polarizability and charge transfer on specific ion effects in the dynamics of aqueous salt solutions.

The diffusion rates for water molecules in salt solutions depend on the identity of the ions, as well as their concentration. Among the alkali metal ions, cesium and potassium increase and sodium strongly decreases the diffusion constant of water. The origin of the difference can be understood by examining the simulation results using different potential models.

Coarse-Grained Models of Aqueous and Pure Liquid Alkanes.

A model for linear alkanes is presented in which interaction sites are only on the carbon atoms, and the range of the potential is reduced using the Stillinger-Weber potential. The model is optimized for aqueous and liquid alkane properties and can match thermodynamic and structural properties, including solvation free energies, liquid densities, and liquid/vapor and liquid/water surface tensions for alkanes over a range of lengths. The results for long alkanes indicate that such models can be useful as accurate, yet efficient, coarse-grained potentials for macromolecules in water and other environments.

Aggregation of cyclic polypeptoids bearing zwitterionic end-groups with attractive dipole-dipole and solvophobic interactions: a study by small-angle neutron scattering and molecular dynamics simulation.

Aggregation behavior of cyclic polypeptoids bearing zwitterionic end-groups in methanol has been studied using a combination of experimental and simulation techniques. The data from SANS and cryo-TEM indicate that the solution contains small clusters of these cyclic polypeptoids, ranging from a single polypeptoid chain to small oligomers, while the linear counterpart shows no cluster formation. Atomistic molecular dynamics simulations reveal that the driving force for this clustering behavior is due to the interplay between the effective repulsion due to the solvation of the dipoles formed by the charged end-groups in each polypeptoid chain and the attractive forces due to dipole-dipole interactions and the solvophobic effect.

Atomistic Study of Intramolecular Interactions in the Closed-State Channelrhodopsin Chimera, C1C2.

Channelrhodopsins (ChR1 and ChR2) are light-activated ion channels that enable photomobility of microalgae from the genus Chlamydomonas. Despite common use of ChR2 in optogenetics for selective control and monitoring of individual neurons in living tissue, the protein structures remain unresolved. Instead, a crystal structure of the ChR chimera (C1C2), an engineered combination of helices I-V from ChR1, without its C-terminus, and helices VI-VII from ChR2, is used as a template for ChR2 structure prediction.

Constant pH simulations of pH responsive polymers.

Polyacidic polymers can change structure over a narrow range of pH in a competition between the hydrophobic effect, which favors a compact state, and electrostatic repulsion, which favors an extended state. Constant pH molecular dynamics computer simulations of poly(methacrylic acid) reveal that there are two types of structural changes, one local and one global, which make up the overall response. The local structural response depends on the tacticity of the polymer and leads to different cooperative effects for polymers with different stereochemistries, demonstrating both positive and negative cooperativities.

Design of Amphiphilic Polymers via Molecular Dynamics Simulations.

Extensive all-atom molecular dynamics simulations were carried out on three novel amphiphilic homopolymers in explicit polar and nonpolar solvent environments. These nonlinear polymers have potential applications in drug delivery and consisted of 32 repeating bifurcated amphiphilic side chains bound to an alkynyl functionalized cyclic framework. All of the polymer systems investigated have the same backbone and hydrophobic dodecyl side chains and differ only in the nature of the hydrophilic side chains.

A polarizable, charge transfer model of water using the drude oscillator.

The transfer of small amounts of charge between neighboring particles can be a significant part of interactions among particles. A model is developed for treating charge transfer (CT) combined with the Drude model for polarizability to create an efficient model for liquid water which includes both CT and polarizability. The model is shown to be accurate for a variety of liquid properties, including the density as a function of temperature and the dielectric constant.

Binding Hydrated Anions with Hydrophobic Pockets.

Using a combination of isothermal titration calorimetry and quantum and molecular dynamics calculations, we demonstrate that relatively soft anions have an affinity for hydrophobic concavity. The results are consistent with the anions remaining partially hydrated upon binding, and suggest a novel strategy for anion recognition.

Charge Transfer Models of Zinc and Magnesium in Water.

Quantum mechanical studies point to the importance of polarization and charge transfer (CT) in zinc binding. A new CT force field is used to study these effects in ion-water dimers and in aqueous solution. Quantum mechanics calculations are carried out to determine amounts of CT.