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Conformational properties of intrinsically disordered proteins (IDPs) are governed by a sequence-ensemble relationship. To differentiate the impact of sequence-local versus sequence-nonlocal features of an IDP's charge pattern on its conformational dimensions and its phase-separation propensity, the charge "blockiness'' $\kappa$ and the nonlocality-weighted sequence charge decoration (SCD) parameters are compared for their correlations with isolated-chain radii of gyration ($R_{\rm g}$s) and upper critical solution temperatures (UCSTs) of polyampholytes modeled by random phase approximation, field-theoretic simulation, and coarse-grained molecular dynamics. SCD is superior to $\kappa$ in predicting $R_{\rm g}$ because SCD accounts for effects of contact order, i.e., nonlocality, on dimensions of isolated chains. In contrast, $\kappa$ and SCD are comparably good, though nonideal, predictors of UCST because frequencies of interchain contacts in the multiple-chain condensed phase are less sensitive to sequence positions than frequencies of intrachain contacts of an isolated chain, as reflected by $\kappa$ correlating better with condensed-phase interaction energy than SCD., Comment: 56 pages, 4 main-text figures, Supporting Information (containing supporting text, 1 supporting table, and 9 supporting figures), Table-of-Contents graphics, and 94 references. Accepted for publication The Journal of Physical Chemistry Letters

Liquid-liquid phase separation (LLPS) involving intrinsically disordered protein regions (IDRs) is a major physical mechanism for biological membraneless compartmentalization. The multifaceted electrostatic effects in these biomolecular condensates are exemplified here by experimental and theoretical investigations of the different salt- and ATP-dependent LLPSs of an IDR of messenger RNA-regulating protein Caprin1 and its phosphorylated variant pY-Caprin1, exhibiting, e.g., reentrant behaviors in some instances but not others. Experimental data are rationalized by physical modeling using analytical theory, molecular dynamics, and polymer field-theoretic simulations, indicating that interchain ion bridges enhance LLPS of polyelectrolytes such as Caprin1 and the high valency of ATP-magnesium is a significant factor for its colocalization with the condensed phases, as similar trends are observed for other IDRs. The electrostatic nature of these features complements ATP's involvement in $\pi$-related interactions and as an amphiphilic hydrotrope, underscoring a general role of biomolecular condensates in modulating ion concentrations and its functional ramifications., Comment: 69 pages, 2 main-text tables, 9 main-text figures, 6 supporting figures, 167 references. Submitted, in revision at eLife

A theory for sequence dependent liquid-liquid phase separation (LLPS) of intrinsically disordered proteins (IDPs) in the study of biomolecular condensates is formulated by extending the random phase approximation (RPA) and field-theoretic simulation (FTS) of heteropolymers with spatially long-range Coulomb interactions to include the fundamental effects of short-range, hydrophobic-like interactions between amino acid residues. To this end, short-range effects are modeled by Yukawa interactions between multiple nonelectrostatic charges derived from an eigenvalue decomposition of pairwise residue-residue contact energies. Chain excluded volume is afforded by incompressibility constraints. A mean-field approximation leads to an effective Flory $\chi$ parameter, which, in conjunction with RPA, accounts for the contact-interaction effects of amino acid composition and the sequence-pattern effects of long-range electrostatics in IDP LLPS, whereas FTS based on the formulation provides full sequence dependence for both short- and long-range interactions. This general approach is illustrated here by applications to variants of a natural IDP in the context of several different amino-acid interaction schemes as well as a set of different model hydrophobic-polar sequences sharing the same composition. Effectiveness of the methodology is verified by coarse-grained explicit-chain molecular dynamics simulations., Comment: 54 pages, 13 figures, 168 references, with typographical errors in previous versions corrected and clarifications added. Accepted for publication in the Journal of Physical Chemistry B

Phase separation of several different overall neutral polyampholyte species (with zero net charge) is studied in solution with two oppositely charged ion species that can form ion-pairs through an association reaction. A field theory description of the system, that treats polyampholyte charge sequence dependent electrostatic interactions as well as excluded volume effects, is hereby given. Interestingly, analysis of the model using random phase approximation and field theoretic simulation consistently show evidence of a re-entrant polyampholyte phase separation at high ion concentrations when there is an overall decrease of volume upon ion-association. As an illustration of the ramifications of our theoretical framework, several polyampholyte concentration vs ion concentration phase diagrams under constant temperature conditions are presented to elucidate the dependence of phase separation behavior on polyampholyte sequence charge pattern as well as ion-pair dissociation constant, volumetric effects on ion association, solvent quality, and temperature., Comment: 15 pages (two-column), 6 figures, 82 references. Minor revisions include added references and Appendix C. Accepted for publication in Journal of Chemical Physics

Biomolecular condensates, physically underpinned to a significant extent by liquid-liquid phase separation (LLPS), are now widely recognized by numerous experimental studies to be of fundamental biological, biomedical, and biophysical importance. In the face of experimental discoveries, analytical formulations emerged as a powerful yet tractable tool in recent theoretical investigations of the role of LLPS in the assembly and dissociation of these condensates. The pertinent LLPS often involves, though not exclusively, intrinsically disordered proteins engaging in multivalent interactions that are governed by their amino acid sequences. For researchers interested in applying these theoretical methods, here we provide a practical guide to a set of computational techniques devised for extracting sequence-dependent LLPS properties from analytical formulations. The numerical procedures covered include those for the determinination of spinodal and binodal phase boundaries from a general free energy function with examples based on the random phase approximation in polymer theory, construction of tie lines for multiple-component LLPS, and field-theoretic simulation of multiple-chain heteropolymeric systems using complex Langevin dynamics. Since a more accurate physical picture often requires comparing analytical theory against explicit-chain model predictions, a commonly utilized methodology for coarse-grained molecular dynamics simulations of sequence-specific LLPS is also briefly outlined., Comment: 46 pages, 10 figures, 105 references, with hyperlinks to relevant computer codes and related information; Figure 8 in version 2 corrected; accepted for publication in "Methods in Molecular Biology" volume "Phase-Separated Biomolecular Condensates" edited by H.-X. Zhou, J.-H. Spille, and P. Banerjee (expected October 2022)

Biomolecular condensates such as membraneless organelles, underpinned by liquid-liquid phase separation (LLPS), are important for physiological function, with electrostatics -- among other interaction types -- being a prominent force in their assembly. Charge interactions of intrinsically disordered proteins (IDPs) and other biomolecules are sensitive to the aqueous dielectric environment. Because the relative permittivity of protein is significantly lower than that of water, the interior of an IDP condensate is a relatively low-dielectric regime, which, aside from its possible functional effects on client molecules, should facilitate stronger electrostatic interactions among the scaffold IDPs. To gain insight into this LLPS-induced dielectric heterogeneity, addressing in particular whether a low-dielectric condensed phase entails more favorable LLPS than that posited by assuming IDP electrostatic interactions are uniformly modulated by the higher dielectric constant of the pure solvent, we consider a simplified multiple-chain model of polyampholytes immersed in explicit solvents that are either polarizable or possess a permanent dipole. Notably, simulated phase behaviors of these systems exhibit only minor to moderate differences from those obtained using implicit-solvent models with a uniform relative permittivity equals to that of pure solvent. Buttressed by theoretical treatments developed here using random phase approximation and polymer field-theoretic simulations, these observations indicate a partial compensation of effects between favorable solvent-mediated interactions among the polyampholytes in the condensed phase and favorable polyampholyte-solvent interactions in the dilute phase, often netting only a minor enhancement of overall LLPS propensity from the very dielectric heterogeneity that arises from the LLPS itself. Further ramifications of this principle are discussed., Comment: 54 pages, 14 figures, 1 table, and 132 references. Accepted for publication in the Journal of Physical Chemistry B ("Liquid-Liquid Phase Separation" Special Issue)

Polyampholyte field theory and explicit-chain molecular dynamics models of sequence-specific phase separation of a system with two intrinsically disordered protein (IDP) species indicate consistently that a substantial polymer excluded volume and a significant mismatch of the IDP sequence charge patterns can act in concert, but not in isolation, to demix the two IDP species upon condensation. This finding reveals an energetic-geometric interplay in a stochastic, "fuzzy" molecular recognition mechanism that may facilitate subcompartmentalization of membraneless organelles., Comment: 39 pages total; 5 figures, 1 table, 1 appendix, 88 references, and 11 supporting figures. Accepted for publication in Physical Review E

A unification of left-right $\rm{SU}(3)_\rm{L}\times \rm{SU}(3)_\rm{R}$, colour $\rm{SU}(3)_\rm{C}$ and family $\rm{SU}(3)_\rm{F}$ symmetries in a maximal rank-8 subgroup of ${\rm{E}}_8$ is proposed as a landmark for future explorations beyond the Standard Model (SM). We discuss the implications of this scheme in a supersymmetric (SUSY) model based on the trinification gauge $\left[\rm{SU}(3)\right]^3$ and global $\rm{SU}(3)_\rm{F}$ family symmetries. Among the key properties of this model are the unification of SM Higgs and lepton sectors, a common Yukawa coupling for chiral fermions, the absence of the $\mu$-problem, gauge couplings unification and proton stability to all orders in perturbation theory. The minimal field content consistent with a SM-like effective theory at low energies is composed of one $\mathrm{E}_6$ $27$-plet per generation as well as three gauge and one family $\rm{SU}(3)$ octets inspired by the fundamental sector of ${\rm{E}}_8$. The details of the corresponding (SUSY and gauge) symmetry breaking scheme, multi-scale gauge couplings' evolution, and resulting effective low-energy scenarios are discussed., Comment: 31 pages, 3 figures; discussion of particle mass hierarchies at low energies expanded; the version accepted to Phys. Rev. D

We describe a class of three Higgs doublet models (3HDMs) with a softly broken $\mathrm{U}(1) \times \mathrm{U}(1)$ family symmetry that enforces a Cabibbo-like quark mixing while forbidding tree-level flavour changing neutral currents. The hierarchy in the observed quark masses is partly explained by a softer hierarchy in the vacuum expectation values of the three Higgs doublets. As a consequence, the physical scalar spectrum contains a Standard Model (SM) like Higgs boson $h_{125}$ while exotic scalars couple the strongest to the second quark family, leading to rather unconventional discovery channels that could be probed at the Large Hadron Collider. In particular, we describe a search strategy for the lightest charged Higgs boson $H^{\pm}$, through the process $c\bar s\to H^{+}\to W^+\,h_{125}$, using a multivariate analysis that leads to an excellent discriminatory power against the SM background. Although the analysis is applied to the proposed class of 3HDMs, we employ a model-independent formulation such that it can be applied to any other model with the same discovery channel., Comment: 30 pages, 7 figures, extended references and added clarifications in the model section. Added Fig. 7 and relevant discussion on the distribution of parameter points in the scan results. Fixed typos and misspellings. Published version

Inspired by a recently proposed GUT model based on the trinification ($\mathrm{SU}(3)^3$) gauge group with a global family ($\mathrm{SU}(3)_F$) symmetry, we consider an effective low-energy three Higgs doublet model that may shed light on what underlies the observed fermion mass hierarchies and CKM mixing. We discuss possibilities for charged scalars coming from this model to show in collider experiments and show some interesting benchmark points., Comment: 7 pages, 2 figures, 5 tables, Proceedings of Prospects for Charged Higgs Discovery at Colliders 2016

We present a supersymmetric (SUSY) model based on trinification $[\mathrm{SU}(3)]^3$ and family $\mathrm{SU}(3)_\mathrm{F}$ symmetries embedded into a maximal subgroup of $\mathrm{E}_8$, where the sectors of light Higgs bosons and leptons are unified into a single chiral supermultiplet. The common origin of gauge trinification and of the family symmetry from $\mathrm{E}_8$ separates the model from other trinification-based GUTs, as it protects, in particular, the Standard Model fermions from gaining mass until the electroweak symmetry is broken. Furthermore, it allows us to break the trinification symmetry via vacuum expectation values in $\mathrm{SU}(3)$-adjoint scalars down to a left-right symmetric theory. Simultaneously, it ensures the unification of the gauge and Yukawa couplings as well as proton stability. Although the low-energy regime (e.g. mass hierarchies in the scalar sector determined by a soft SUSY-breaking mechanism) is yet to be established, these features are one key to revive the once very popular trinification-based GUTs., Comment: 6 pages; published version

Using the one-loop Coleman-Weinberg effective potential, we derive a general analytic expression for all the derivatives of the effective potential with respect to any number of classical scalar fields. The result is valid for a renormalisable theory in four dimensions with any number of scalars, fermions or gauge bosons. This result corresponds to the zero-external momentum contribution to a general one-loop diagram with N scalar external legs. We illustrate the use of the general result in two simple scalar singlet extensions of the Standard Model, to obtain the dominant contributions to the triple couplings of light scalar particles under the zero external momentum approximation, Comment: 26 pages, 2 figures. Minor text improvements and new references added. To appear in JHEP

In this work, we present a trinification-based grand unified theory incorporating a global $\mathrm{SU}(3)$ family symmetry that after a spontaneous breaking leads to a left-right symmetric model. Already at the classical level, this model can accommodate the matter content and the quark Cabbibo mixing in the Standard Model (SM) with only one Yukawa coupling at the unification scale. Considering the minimal low-energy scenario with the least amount of light states, we show that the resulting effective theory enables dynamical breaking of its gauge group down to that of the SM by means of radiative corrections accounted for by the renormalisation group evolution at one loop. This result paves the way for a consistent explanation of the SM breaking scale and fermion mass hierarchies., Comment: 39 pages, 6 figures. Added a discussion (Sect. 7.2) on 1-loop contributions to the masses of light scalars. Published version

The self-assembly of proteins into $\beta$-sheet-rich amyloid fibrils has been observed to occur with sigmoidal kinetics, indicating that the system initially is trapped in a metastable state. Here, we use a minimal lattice-based model to explore the thermodynamic forces driving amyloid formation in a finite canonical ($NVT$) system. By means of generalized-ensemble Monte Carlo techniques and a semi-analytical method, the thermodynamic properties of this model are investigated for different sets of intersheet interaction parameters. When the interactions support lateral growth into multi-layered fibrillar structures, an evaporation/condensation transition is observed, between a supersaturated solution state and a thermodynamically distinct state where small and large fibril-like species exist in equilibrium. Intermediate-size aggregates are statistically suppressed. These properties do not hold if aggregate growth is one-dimensional., Comment: 22 pages