Active responsive colloids coupled to different thermostats.

We introduce a model of active responsive colloids (ARCs) in which an internal degree of freedom (DoF) of a single colloidal particle is "activated" by coupling it to a different thermostat than for the translational DoFs. As for the responsive internal DoF, we consider specifically the size (diameter) of the spherical particles, which is confined by a harmonic parent potential being either entropic or energetic in nature. The ARCs interact via a repulsive Hertzian pair potential, appropriate to model hydrogels or elastic colloids, and are studied for various densities using Brownian dynamics simulations. We tune the internal activity in the nonequilibrium steady state by scanning through a wide range of internal temperatures, both smaller ("colder") and larger ("hotter") than the translational temperature. The results show a rich and intriguing behavior for the emergent property distributions, colloidal pair structure, and the diffusive translational dynamics controlled by the internal activity, substantially depending on whether the internal DoF moves in an entropic or energetic potential. We discuss theoretical thermal limits and phenomenological models which can explain some of the nonequilibrium trends qualitatively. Our study indicates that particle dynamical polydispersity as well as the structure and dynamics of dense macromolecular suspensions can be vastly tuned by internal activity in terms of internal "hot" or "cold" fluctuating states.

Active responsive colloids driven by intrinsic dichotomous noise.

We study the influence of intrinsic noise on the structure and dynamics of responsive colloids (RCs), which actively change their size and mutual interactions. The colloidal size is explicitly resolved in our RC model as an internal degree of freedom (DOF) in addition to the particle translation. A Hertzian pair potential between the RCs leads to repulsion and shrinking of the particles, resulting in an explicit responsiveness of the system to self-crowding. To render the colloids active, their size is internally driven by a dichotomous noise, randomly switching ("breathing") between growing and shrinking states with a predefined rate, as motivated by recent experiments on synthetic active colloids. The polydispersity of this dichotomous active responsive colloid (D-ARC) model can be tuned by the parameters of the noise. Utilizing stochastic computer simulations, we study crowding effects on the spatial distributions, relaxation times, and self-diffusion of dense suspensions of the D-ARCs. We find a substantial influence of the "built-in" intrinsic noise on the system's behavior, in particular, transitions from unimodal to bimodal size distributions for an increasing colloid density as well as intrinsic noise-modified diffusive translational dynamics. We conclude that controlling the noise of internal DOFs of a macromolecule or cell is a powerful tool for active colloidal materials to enable autonomous changes in the system's collective structure and dynamics towards the adaptation of macroscopic properties to external perturbations.

Controlling solvent quality by time: Self-avoiding sprints in nonequilibrium polymerization.

A fundamental paradigm in polymer physics is that macromolecular conformations in equilibrium can be described by universal scaling laws, being key for structure, dynamics, and function of soft (biological) matter and in the materials sciences. Here we reveal that during diffusion-influenced, nonequilibrium chain-growth polymerization, scaling laws change qualitatively, in particular, the growing polymers exhibit a surprising self-avoiding walk behavior in poor and θ solvents. Our analysis, based on monomer-resolved, off-lattice reaction-diffusion computer simulations, demonstrates that this phenomenon is a result of (i) nonequilibrium monomer density depletion correlations around the active polymerization site, leading to a locally directed and self-avoiding growth, in conjunction with (ii) chain (Rouse) relaxation times larger than the competing polymerization reaction time. These intrinsic nonequilibrium mechanisms are facilitated by fast and persistent reaction-driven diffusion ("sprints") of the active site, with analogies to pseudochemotactic active Brownian particles. Our findings have implications for time-controlled structure formation in polymer processing, as in, e.g., reactive self-assembly, photocrosslinking, and three-dimensional printing.

Structure and dynamics of responsive colloids with dynamical polydispersity.

Dynamical polydispersity in single-particle properties, for example a fluctuating particle size, shape, charge density, etc, is intrinsic to responsive colloids (RCs), such as biomacromolecules or microgels, but is typically not resolved in coarse-grained mesoscale simulations. Here, we present Brownian dynamics simulations of suspensions of RCs modeling soft hydrogel colloids, for which the size of the individual particles is an explicitly resolved (Gaussian) degree of freedom and dynamically responds to the local interacting environment. We calculate the liquid structure, emergent size distributions, long-time diffusion, and property (size) relaxation kinetics for a wide range of densities and intrinsic property relaxation times in the canonical ensemble. Comparison to interesting reference cases, such as conventional polydisperse suspensions with a frozen parent distribution, or conventional monodisperse systems interacting with an effective pair potential for one fixed size, shows a significant spread in the structure and dynamics. The differences, most apparent in the high density regimes, are due to many-body correlations and the dynamical coupling between property and translation in RC systems, not explicitly accounted for in the conventional treatments. In particular, the translational diffusion in the RC systems is surprisingly close to the free (single RC) diffusion, mainly due to a cancellation of crowding and size compression effects. We show that an effective monodisperse pair potential can be constructed that describes the many-body correlations reasonably well by convoluting the RC pair potential with the density-dependent emergent size distributions and using a mean effective diffusion constant.

Modulating internal transition kinetics of responsive macromolecules by collective crowding.

Packing and crowding are used in biology as mechanisms to (self-)regulate internal molecular or cellular processes based on collective signaling. Here, we study how the transition kinetics of an internal "switch" of responsive macromolecules is modified collectively by their spatial packing. We employ Brownian dynamics simulations of a model of Responsive Colloids, in which an explicit internal degree of freedom-here, the particle size-moving in a bimodal energy landscape self-consistently responds to the density fluctuations of the crowded environment. We demonstrate that populations and transition times for the two-state switching kinetics can be tuned over one order of magnitude by "self-crowding." An exponential scaling law derived from a combination of Kramers' and liquid state perturbation theory is in very good agreement with the simulations.

Thermal Compaction of Disordered and Elastin-like Polypeptides: A Temperature-Dependent, Sequence-Specific Coarse-Grained Simulation Model.

Elastin-like polypeptides (ELPs) undergo a sharp solubility transition from low-temperature solvated phases to coacervates at elevated temperatures, driven by the increased strength of hydrophobic interactions at higher temperatures. The transition temperature, or "cloud point", critically depends on sequence composition, sequence length, and concentration of the ELPs. In this work, we present a temperature-dependent, implicit solvent, sequence-specific coarse-grained (CG) simulation model that reproduces the transition temperatures as a function of sequence length and guest residue identity of various experimentally probed ELPs to appreciable accuracy. Our model builds upon the self-organized polymer model introduced recently for intrinsically disordered polypeptides (SOP-IDP) and introduces a semi-empirical functional form for the temperature dependence of hydrophobic interactions. In addition to the fine performance for various ELPs, we demonstrate the ability of our model to capture the thermal compactions in dominantly hydrophobic IDPs, consistent with experimental scattering data. With the high computational efficiency afforded by the CG representation, we envisage that the model will be ideally suited for simulations of large-scale structures such as ELP networks and hydrogels, as well as agglomerates of IDPs.

Aggregation dynamics of charged peptides in water: Effect of salt concentration.

Extensive molecular dynamics simulations have been employed to probe the effects of salts on the kinetics and dynamics of early-stage aggregated structures of steric zipper peptides in water. The simulations reveal that the chemical identity and valency of cation in the salt play a crucial role in aggregate dynamics and morphology of the peptides. Sodium ions induce the most aggregated structures, but this is not replicated equivalently by potassium ions which are also monovalent. Divalent magnesium ions induce aggregation but to a lesser extent than that of sodium, and their interactions with the charged peptides are also significantly different. The aggregate morphology in the presence of monovalent sodium ions is a compact structure with interpenetrating peptides, which differs from the more loosely connected peptides in the presence of either potassium or magnesium ions. The different ways in which the cations effectively renormalize the charges of peptides are suggested to be the cause of the differential effects of different salts studied here. These simulations underscore the importance of understanding both the valency and nature of salts in biologically relevant aggregated structures.

Sequence Effects on Size, Shape, and Structural Heterogeneity in Intrinsically Disordered Proteins.

Intrinsically disordered proteins (IDPs) lack well-defined three-dimensional structures, thus challenging the archetypal notion of structure-function relationships. Determining the ensemble of conformations that IDPs explore under physiological conditions is the first step toward understanding their diverse cellular functions. Here, we quantitatively characterize the structural features of IDPs as a function of sequence and length using coarse-grained simulations. For diverse IDP sequences, with the number of residues ( NT) ranging from 20 to 441, our simulations not only reproduce the radii of gyration ( Rg) obtained from experiments, but also predict the full scattering intensity profiles in excellent agreement with small-angle X-ray scattering experiments. The Rg values are well-described by the standard Flory scaling law, Rg = Rg0 NTν, with ν ≈ 0.588, making it tempting to assert that IDPs behave as polymers in a good solvent. However, clustering analysis reveals that the menagerie of structures explored by IDPs is diverse, with the extent of heterogeneity being highly sequence-dependent, even though ensemble-averaged properties, such as the dependence of Rg on chain length, may suggest synthetic polymer-like behavior in a good solvent. For example, we show that for the highly charged Prothymosin-α, a substantial fraction of conformations is highly compact. Even if the sequence compositions are similar, as is the case for α-Synuclein and a truncated construct from the Tau protein, there are substantial differences in the conformational heterogeneity. Taken together, these observations imply that metrics based on net charge or related quantities alone cannot be used to anticipate the phases of IDPs, either in isolation or in complex with partner IDPs or RNA. Our work sets the stage for probing the interactions of IDPs with each other, with folded protein domains, or with partner RNAs, which are critical for describing the structures of stress granules and biomolecular condensates with important cellular functions.

Synergy between intrinsically disordered domains and structured proteins amplifies membrane curvature sensing.

The ability of proteins to sense membrane curvature is essential to cellular function. All known sensing mechanisms rely on protein domains with specific structural features such as wedge-like amphipathic helices and crescent-shaped BAR domains. Yet many proteins that contain these domains also contain large intrinsically disordered regions. Here we report that disordered domains are themselves potent sensors of membrane curvature. Comparison of Monte Carlo simulations with in vitro and live-cell measurements demonstrates that the polymer-like behavior of disordered domains found in endocytic proteins drives them to partition preferentially to convex membrane surfaces, which place fewer geometric constraints on their conformational entropy. Further, proteins containing both structured curvature sensors and disordered regions are more than twice as curvature sensitive as their respective structured domains alone. These findings demonstrate an entropic mechanism of curvature sensing that is independent of protein structure and illustrate how structured and disordered domains can synergistically enhance curvature sensitivity.

Influence of lipid composition of model membranes on methacrylate antimicrobial polymer-membrane interactions.

Using atomistic molecular dynamics simulations, the role of lipid composition in the interactions of multiple methacrylate antimicrobial polymer agents with model membranes, and the consequent response of the membranes is studied. In our earlier study, methacrylate polymers were observed to induce phase demixing and associated thickness mismatch in a POPE-POPG model microbial membrane. In this work, we probe (1) the role of varying the degree of saturation in lipid acyl chains in the membrane interactions of methacrylate polymers, and (2) whether electrostatics (addition of anionic lipids) can influence the interactions of the polymers with model mammalian membranes. Lipid composition is observed to significantly modify membrane-polymer interactions, leading to differences in both the mode of partitioning and the conformations adopted by the polymers, in addition to impacting membrane properties differently. The results strongly suggest that the oft-cited electrostatic interactions between the antimicrobial agents and the microbial membranes do not fully account for the recognition and subsequent partitioning of the antimicrobial agents. The ability of the methacrylate polymers to sense interfacial lipid packing defects, determined by the PE/PC head groups of lipids, is also found to be influential in their membrane partitioning. Deliberate inclusion of charged anionic lipids into a model mammalian membrane, leading to additional favorable electrostatics, does not reproduce a similar polymer partitioning mechanism to that in its microbial counterpart. The differences observed in the interactions of methacrylate polymers with the various model membranes can be instrumental in extending our understanding of underlying modes of membrane disruption by general antimicrobial agents as well.

Effect of simple solutes on the long range dipolar correlations in liquid water.

Intermolecular correlations in liquid water at ambient conditions have generally been characterized through short range density fluctuations described through the atomic pair distribution functions. Recent numerical and experimental results have suggested that such a description of order or structure in liquid water is incomplete and there exist considerably longer ranged orientational correlations in water that can be studied through dipolar correlations. In this study, using large scale classical, atomistic molecular dynamics simulations using TIP4P-Ew and TIP3P models of water, we show that salts such as sodium chloride (NaCl), potassium chloride (KCl), caesium chloride (CsCl), and magnesium chloride (MgCl2) have a long range effect on the dipolar correlations, which cannot be explained by the notion of structure making and breaking by dissolved ions. Observed effects are explained through orientational stratification of water molecules around ions and their long range coupling to the global hydrogen bond network by virtue of the sum rule for water. The observations for single hydrophilic solutes are contrasted with the same for a single methane (CH4) molecule. We observe that even a single small hydrophobe can result in enhancement of long range orientational correlations in liquid water, contrary to the case of dissolved ions, which have been observed to have a reducing effect. The observations from this study are discussed in the context of hydrophobic effect.

Ion hydration and associated defects in hydrogen bond network of water: observation of reorientationally slow water molecules beyond first hydration shell in aqueous solutions of MgCl2.

Effects of the presence of ions, at moderate to high concentrations, on dynamical properties of water molecules are investigated through classical molecular dynamics simulations using two well-known nonpolarizable water models. Simulations reveal that the presence of magnesium chloride (MgCl(2)) induces perturbations in the hydrogen bond network of water leading to the formation of bulklike domains with ''defect sites'' on boundaries of such domains: water molecules at such defect sites have less number of hydrogen bonds than those in bulk water. Reorientational autocorrelation functions for dipole vectors of such defect water molecules are computed at different concentrations of ions and compared with system of pure water. Earlier experimental and simulation studies indicate significant differences in reorientational dynamics for water molecules in the first hydration shell of many dissolved ions. Results of this study suggest that defect water molecules, which are beyond the first hydration shells of ions, also experience significant slowing of reorientation times as a function of concentration in the case of MgCl(2). However, addition of cesium chloride (CsCl) to water does not perturb the hydrogen bond network of water significantly even at higher concentrations. This difference in behavior between MgCl(2) and CsCl is consistent with the well-known Hofmeister series.

Interaction of multiple biomimetic antimicrobial polymers with model bacterial membranes.

Using atomistic molecular dynamics simulations, interaction of multiple synthetic random copolymers based on methacrylates on prototypical bacterial membranes is investigated. The simulations show that the cationic polymers form a micellar aggregate in water phase and the aggregate, when interacting with the bacterial membrane, induces clustering of oppositely charged anionic lipid molecules to form clusters and enhances ordering of lipid chains. The model bacterial membrane, consequently, develops lateral inhomogeneity in membrane thickness profile compared to polymer-free system. The individual polymers in the aggregate are released into the bacterial membrane in a phased manner and the simulations suggest that the most probable location of the partitioned polymers is near the 1-palmitoyl-2-oleoyl-phosphatidylglycerol (POPG) clusters. The partitioned polymers preferentially adopt facially amphiphilic conformations at lipid-water interface, despite lacking intrinsic secondary structures such as α-helix or ß-sheet found in naturally occurring antimicrobial peptides.