Chain-growth Method Research Articles

Statistical accuracy of molecular dynamics-based methods for sampling conformational ensembles of disordered proteins.

The characterization of the statistical ensemble of conformations of intrinsically disordered regions (IDRs) is a great challenge both from experimental and computational points of view. In this respect, a number of protocols have been developed using molecular dynamics (MD) simulations to sample the huge conformational space of the molecule. In this work, we consider one of the best methods available, replica exchange solute tempering (REST), as a reference to compare the results obtained using this method with the results obtained using other methods, in terms of experimentally measurable quantities. Along with the methods assessed, we propose here a novel protocol called probabilistic MD chain growth (PMD-CG), which combines the flexible-meccano and hierarchical chain growth methods with the statistical data obtained from tripeptide MD trajectories as the starting point. The system chosen for testing is a 20-residue region from the C-terminal domain of the p53 tumor suppressor protein (p53-CTD). Our results show that PMD-CG provides an ensemble of conformations extremely quickly, after suitable computation of the conformational pool for all peptide triplets of the IDR sequence. The measurable quantities computed on the ensemble of conformations agree well with those based on the REST conformational ensemble.

Rethinking Catalyst Trapping in Ni-Catalyzed Thieno[3,2-b]thiophene Polymerization.

Catalyst-transfer polymerization (CTP) is a chain-growth method used to synthesize conjugated polymers. Although CTP works well for most donor-type monomers, the polymerization stalls with thieno[3,2-b]thiophene when using Ni catalysts. Previous reports have rationalized this result by suggesting that the catalyst is trapped in a Ni0 π-complex with the highly electron-rich arene. In this study, evidence is provided that the catalyst trap is more likely a NiII complex that arises from oxidative insertion of Ni0 into the C-S bonds of thieno[3,2-b]thiophene. This result is consistent with the known reactivity of Ni0 complexes toward S-heteroarenes and is supported herein by 31P nuclear magnetic resonance spectra acquired in situ, as well as data collected from small-molecule model reactions and density-functional theory simulations of the polymerization. We propose that this C-S insertion pathway and related off-cycle reactions may be relevant to understanding or enabling the CTP of other monomers with fused thiophenes.

A Chain-Growth Mechanism for Conjugated Polymer Synthesis Facilitated by Dinuclear Complexes with Redox-Active Ligands.

Conjugated polymers are widely used in energy conversion and sensor applications, but their synthesis relies on imprecise step-growth or narrow-scope chain-growth methods, typically based on transition metal (TM)-catalyzed cross-coupling. Here we report that a dinickel complex with a redox-active naphthyridine diimine ligand accesses new chain-growth mechanistic manifolds for both donor and acceptor conjugated polymers, represented by poly(3-hexylthiophene), poly(2,3-bis(2-ethylhexyl)thienopyrazine), and poly(2-(2-octyldodecyl)benzotriazole). For the latter, our method is particularly effective: we achieve high degrees of polymerization (DP) (>100) with moderate dispersities (Đ) of ≈1.4. Mechanistic analysis supports a radical/radical anion chain-growth mechanism with organometallic intermediates instead of TM-catalyzed cross-couplings. Hence, our work develops new mechanisms for conjugated polymer synthesis and furnishes insights about the elementary reactivity of dinuclear complexes.

Three Ways to Polyamides: The Impact of Polymerization Mechanism on Polymer Properties

Polymer chemistry lab experiments present a unique opportunity to allow students to experience the consequences of reaction mechanisms on the properties of the resulting product. In this organic chemistry experiment, students prepared a polyamide by three different reaction mechanisms that represent step-growth and chain-growth methods of polymerization: melt polycondensation of an amine and a carboxylic acid, interfacial polymerization of an amine and an acid chloride, and ring-opening polymerization of a lactam. Characterizing the polymers by both FTIR spectroscopy and differential scanning calorimetry requires students to consider how the choice of mechanism affects conversion of monomer to polymer, the resulting crystallinity of that polymer, and the challenges that must be overcome when setting up and executing the polymerization procedure.

Mechanistic Insight into Thiophene Catalyst-Transfer Polymerization Mediated by Nickel Diimine Catalysts

Catalyst-transfer polymerization (CTP) is a living, chain-growth method for accessing conjugated polymers with control over their length and sequence. Typical catalysts utilized in CTP are either Pd or Ni complexes with bisphosphine or N-heterocyclic carbene ancillary ligands. More recently, diimine-ligated Ni complexes have been employed; however, in most cases nonliving pathways become dominant at high monomer conversions and/or low catalyst loading. We report herein an alternative Ni diimine catalyst that polymerizes 3-hexylthiophene in a chain-growth manner at low catalyst loading and high monomer conversion. In addition, we elucidate the chain-growth mechanism as well as one chain-transfer pathway. Overall, these studies provide insight into the mechanism of conjugated polymer synthesis mediated by Ni diimine catalysts.

Fenton-RAFT Polymerization: An "On-Demand" Chain-Growth Method.

Fine control over the architecture and/or microstructure of synthetic polymers is fast becoming a reality owing to the development of efficient and versatile polymerization techniques and conjugation reactions. However, the transition of these syntheses to automated, programmable, and high-throughput operating systems is a challenging step needed to translate the vast potential of precision polymers into machine-programmable polymers for biological and functional applications. Chain-growth polymerizations are particularly appealing for their ability to form structurally and chemically well-defined macromolecules through living/controlled polymerization techniques. Even using the latest polymerization technologies, the macromolecular engineering of complex functional materials often requires multi-step syntheses and purification of intermediates, and results in sub-optimal yields. To develop a proof-of-concept of a framework polymerization technique that is readily amenable to automation requires several key characteristics. In this study, a new approach is described that is believed to meet these requirements, thus opening avenues toward automated polymer synthesis.

Conjugated Polymers with Switchable Carrier Polarity

Stimuli responsive polymers can change their properties as a result of their environment. Factors such as temperature, light, pH, or solvent can all trigger a polymer response. We present conjugated polymers with switchable carrier polarity, accomplished using a functional group that can be converted from electron donating to electron withdrawing. The polymers presented herein are polyselenophenes containing α-ketal side-chains. The α-ketal side-chains can be converted to electron withdrawing α-ketone side-chains postpolymerization. Since the starting monomer is relatively electron-rich, it can be polymerized using chain growth methods. Switching the electron donating ability of the side chain postpolymerization is an effective way to synthesize electron-deficient conjugated polymers from electron-rich monomers. Whereas the α-ketal polymer has optoelectronic properties that are consistent with other electron-rich (p-type) polymers, the α-keto polymer features a broad red optical-absorption, narrow HOMO–LU...

Conjugated Polymer Synthesis via Catalyst-Transfer Polycondensation (CTP): Mechanism, Scope, and Applications

The recent discovery of a living, controlled chain-growth method for synthesizing π-conjugated polymers has ignited the field and led to the development of many new materials. This Perspective focuses on the mechanistic underpinnings of the synthetic transformation, highlighting the controversial hypotheses and supporting data. A critical analysis of the literature revealed that the monomer scope remains largely limited to electron-rich monomers at this time. Last, a brief overview of some exciting new materials accessed via this method is provided.

Conformational Properties of Polymers Near a Fractal Surface

Abstract The conformational properties of flexible polymer macromolecules grafted to an attractive partially penetrable surface with fractal dimension d pc s =91/49 are studied. Employing computer simulations based on the prunedenriched Rosenbluth chain-growth method, estimates for the surface crossover exponent and adsorption transition temperature are found. Our results quantitatively reveal the slowing down of the adsorption process caused by the fractal self-similar structure of the underlying substrate.

Θ-polymers in crowded media under stretching force

We study the peculiarities of stretching of globular polymer macromolecules in a disordered (crowded) environment, using the model of self-attracting self-avoiding walks on site-diluted percolative lattices in space dimensions d = 3 . Applying the pruned–enriched Rosenbluth chain-growth method (PERM), we construct the phase diagram of collapsed–extended state coexistence when varying temperature and stretching force. The change in shape characteristics of globular polymers under stretching is analyzed as well.

Fractals meet fractals: self-avoiding random walks on percolation clusters

The scaling behavior of linear polymers in disordered media, modelled by self-avoiding walks (SAWs) on the backbone of percolation clusters in two, three and four dimensions is studied by numerical simulations. We apply the pruned-enriched Rosenbluth chain-growth method (PERM). Our numerical results yield estimates of critical exponents, governing the scaling laws of disorder averages of the configurational properties of SAWs, and clearly indicate a multifractal spectrum which emerges when two fractals meet each other.

Polymers in crowded environment under stretching force: Globule-coil transitions

We study flexible polymer macromolecules in a crowded (porous) environment, modeling them as self-attracting self-avoiding walks on site-diluted percolative lattices in space dimensions d=2,3 . The influence of stretching force on the polymer folding and the properties of globule-coil transitions are analyzed. Applying the pruned-enriched Rosenbluth chain-growth method, we estimate the transition temperature TTheta between collapsed and extended polymer configurations and construct the phase diagrams of the globule-coil coexistence when varying temperature and stretching force. The transition to a completely stretched state, caused by applying force, is discussed as well.

Freezing and collapse of flexible polymers on regular lattices in three dimensions

We analyze the crystallization and collapse transition of a simple model for flexible polymer chains on simple-cubic and face-centered-cubic lattices by means of sophisticated chain-growth methods. In contrast to the bond-fluctuation polymer model in certain parameter ranges, where these two conformational transitions were found to merge in the thermodynamic limit, we conclude from our results that the two transitions remain well separated in the limit of infinite chain lengths. The reason for this qualitatively distinct behavior is presumably due to the ultrashort attractive interaction range in the lattice models considered here.

Importance of chirality and reduced flexibility of protein side chains: a study with square and tetrahedral lattice models.

Side chains of amino acid residues are the determining factor that distinguishes proteins from other unstable chain polymers. In simple models they are often represented implicitly (e.g., by spin states) or simplified as one atom. Here we study side chain effects using two-dimensional square lattice and three-dimensional tetrahedral lattice models, with explicitly constructed side chains formed by two atoms of different chirality and flexibility. We distinguish effects due to chirality and effects due to side chain flexibilities, since residues in proteins are L residues, and their side chains adopt different rotameric states. For short chains, we enumerate exhaustively all possible conformations. For long chains, we sample effectively rare events such as compact conformations and obtain complete pictures of ensemble properties of conformations of these models at all compactness region. This is made possible by using sequential Monte Carlo techniques based on chain growth method. Our results show that both chirality and reduced side chain flexibility lower the folding entropy significantly for globally compact conformations, suggesting that they are important properties of residues to ensure fast folding and stable native structure. This corresponds well with our finding that natural amino acid residues have reduced effective flexibility, as evidenced by statistical analysis of rotamer libraries and side chain rotatable bonds. We further develop a method calculating the exact side chain entropy for a given backbone structure. We show that simple rotamer counting underestimates side chain entropy significantly for both extended and near maximally compact conformations. We find that side chain entropy does not always correlate well with main chain packing. With explicit side chains, extended backbones do not have the largest side chain entropy. Among compact backbones with maximum side chain entropy, helical structures emerge as the dominating configurations. Our results suggest that side chain entropy may be an important factor contributing to the formation of alpha helices for compact conformations.

Multicanonical chain-growth algorithm.

We present a temperature-independent Monte Carlo method for the determination of the density of states of lattice proteins that combines the fast ground-state search strategy of the new pruned-enriched Rosenbluth chain-growth method and multicanonical reweighting for sampling the complete energy space. Since the density of states contains all energetic information of a statistical system, we can directly calculate the mean energy, specific heat, Helmholtz free energy, and entropy for all temperatures. We apply this method to lattice proteins consisting of hydrophobic and polar monomers, and for the examples of sequences considered, we identify the transitions between native, globule, and random coil states. Since no special properties of heteropolymers are involved in this algorithm, the method applies to polymer models as well.

Growth algorithms for lattice heteropolymers at low temperatures

Two improved versions of the pruned-enriched-Rosenbluth method (PERM) are proposed and tested on simple models of lattice heteropolymers. Both are found to outperform not only the previous version of PERM, but also all other stochastic algorithms which have been employed on this problem, except for the core directed chain growth method (CG) of Beutler and Dill. In nearly all test cases they are faster in finding low-energy states, and in many cases they found new lowest energy states missed in previous papers. The CG method is superior to our method in some cases, but less efficient in others. On the other hand, the CG method uses heavily heuristics based on presumptions about the hydrophobic core and does not give thermodynamic properties, while the present method is a fully blind general purpose algorithm giving correct Boltzmann–Gibbs weights, and can be applied in principle to any stochastic sampling problem.

A fast conformational search strategy for finding low energy structures of model proteins

We describe a new computer algorithm for finding low-energy conformations of proteins. It is a chain-growth method that uses a heuristic bias function to help assemble a hydrophobic core. We call it the Core-directed chain Growth method (CG). We test the CG method on several well-known literature examples of HP lattice model proteins [in which proteins are modeled as sequences of hydrophobic (H) and polar (P) monomers], ranging from 20-64 monomers in two dimensions, and up to 88-mers in three dimensions. Previous nonexhaustive methods--Monte Carlo, a Genetic Algorithm, Hydrophobic Zippers, and Contact Interactions--have been tried on these same model sequences. CG is substantially better at finding the global optima, and avoiding local optima, and it does so in comparable or shorter times. CG finds the global minimum energy of the longest HP lattice model chain for which the global optimum is known, a 3D 88-mer that has only been reachable before by the CHCC complete search method. CG has the potential advantage that it should have nonexponential scaling with chain length. We believe this is a promising method for conformational searching in protein folding algorithms.

Biasing a Monte Carlo chain growth method with Ramachandran's plot: Application to twenty‐L‐alanine

In this paper, we explore the possibility of using experimental observations in the Monte Carlo chain growth method that we have previously developed. In this method, the macromolecule (peptide, protein, nuclei acid, etc.) is grown atom-by-atom (or residue-by-residue, etc.) and partial chains are replicated according to their Boltzmann weights. Once the molecule completed, we are left with a Boltzmann-distributed ensemble of configurations. For long molecules, an efficient sampling of the (extremely large) phase space is difficult for obvious reasons (existence of many local minima, limited computer memory, etc.). In the case in which one is mainly interested in the low energy conformations, we have incorporated in the growth scheme experimental observations taken from the Protein Data Banks. More precisely, we have considered the case of twenty-L-alanine and we have used the (experimental) Ramachandran's plot for this residue. The biased growth procedure goes as follows: (a) each time one adds along the main backbone chain, either a carbon atom belonging to a carbonyl group, or a nitrogen atom, its dihedral angle (theta) or (psi) is drawn with a probability law that reflects the experimental Ramachandran (theta, psi) plot; (b) the bias introduced in this way is canceled through an extra term in the energy (replication energy = true energy + bias energy); (c) the configurations, generated at T = 1000 K, are then energy minimized.(ABSTRACT TRUNCATED AT 250 WORDS)