arXiv subjects

Hue Sun Chan

Publications and source records attributed to Hue Sun Chan.

29 records · Page 2Linked to original sources

arXiv2017

Phase separation and single-chain compactness of charged disordered proteins are strongly correlated

Liquid-liquid phase separation of intrinsically disordered proteins (IDPs) is a major undergirding factor in the regulated formation of membraneless organelles in the cell. The phase behavior of an IDP is sensitive to its amino acid sequence. Here we apply a recent random-phase-approximation polymer theory to investigate how the tendency for multiple chains of a protein to phase separate, as characterized by the critical temperature $T^*_{\rm cr}$, is related to the protein's single-chain average radius of gyration $\langle R_{\rm g} \rangle$. For a set of sequences containing different permutations of an equal number of positively and negatively charged residues, we found a striking correlation $T^*_{\rm cr}\sim \langle R_{\rm g} \rangle^{-γ}$ with $γ$ as large as $\sim 6.0$, indicating that electrostatic effects have similarly significant impact on promoting single-chain conformational compactness and phase separation. Moreover, $T^*_{\rm cr}\propto -{\rm SCD}$, where SCD is a recently proposed "sequence charge decoration" parameter determined solely by sequence information. Ramifications of our findings for deciphering the sequence dependence of IDP phase separation are discussed.

q-bio.BM↗

arXiv2016

Random-phase-approximation theory for sequence-dependent, biologically functional liquid-liquid phase separation of intrinsically disordered proteins

Intrinsically disordered proteins (IDPs) are typically low in nonpolar/hydrophobic but relatively high in polar, charged, and aromatic amino acid compositions. Some IDPs undergo liquid-liquid phase separation in the aqueous milieu of the living cell. The resulting phase with enhanced IDP concentration can function as a major component of membraneless organelles that, by creating their own IDP-rich microenvironments, stimulate critical biological functions. IDP phase behaviors are governed by their amino acid sequences. To make progress in understanding this sequence-phase relationship, we report further advances in a recently introduced application of random-phase-approximation (RPA) heteropolymer theory to account for sequence-specific electrostatics in IDP phase separation. Here we examine computed variations in phase behavior with respect to block length and charge density of model polyampholytes of alternating equal-length charge blocks to gain insight into trends observed in IDP phase separation. As a real-life example, the theory is applied to rationalize/predict binodal and spinodal phase behaviors of the 236-residue N-terminal disordered region of RNA helicase Ddx4 and its charge-scrambled mutant for which experimental data are available. Fundamental differences are noted between the phase diagrams predicted by RPA and those predicted by mean-field Flory-Huggins and Overbeek-Voorn/Debye-Hückel theories. In the RPA context, a physically plausible dependence of relative permittivity on protein concentration can produce a cooperative effect in favor of IDP-IDP attraction and thus a significant increased tendency to phase separate. Ramifications of these findings for future development of IDP phase separation theory are discussed.

q-bio.BM↗

arXiv2016

Sequence-specific polyampholyte phase separation in membraneless organelles

Liquid-liquid phase separation of charge/aromatic-enriched intrinsically disordered proteins (IDPs) is critical in the biological function of membraneless organelles. Much of the physics of this recent discovery remains to be elucidated. Here we present a theory in the random phase approximation to account for electrostatic effects in polyampholyte phase separations, yielding predictions consistent with recent experiments on the IDP Ddx4. The theory is applicable to any charge pattern and thus provides a general analytical framework for studying sequence dependence of IDP phase separation.

q-bio.BM↗

arXiv2003

Simple Two-State Protein Folding Kinetics Requires Near-Levinthal Thermodynamic Cooperativity

Simple two-state folding kinetics of many small single-domain proteins are characterized by chevron plots with linear folding and unfolding arms consistent with a two-state description of equilibrium thermodynamics. This phenomenon is hereby recognized as a nontrivial heteropolymer property capable of providing fundamental insight into protein energetics. Many current protein chain models, including common lattice and continuum Gō models with explicit native biases, fail to reproduce this generic protein property. Here we show that simple two-state kinetics is obtainable from models with a cooperative interplay between core burial and local conformational propensities or an extra strongly favorable energy for the native structure. These predictions suggest that intramolecular recognition in real two-state proteins is more specific than that envisioned by common Gō-like constructs with pairwise additive energies. The many-body interactions in the present kinetically two-state models lead to high thermodynamic cooperativity as measured by their van't Hoff to calorimetric enthalpy ratios, implying that the native and denatured conformational populations are well separated in enthalpy by a high free energy barrier. Consistent with experiments, comparison among the present models with extra native favorabilities indicate that their folding rate at a given interaction strength decreases with increasing native contact order, although the dependence is weaker than the corresponding trend in real proteins. It has been observed experimentally that deviations from Arrhenius behavior are often more severe for folding than for unfolding. This asymmetry may be rationalized by one ...

cond-mat.soft↗

arXiv2003

Energetics of Protein Thermodynamic Cooperativity: Contributions of Local and Nonlocal Interactions

The respective roles of local and nonlocal interactions in the thermodynamic cooperativity of proteins are investigated using continuum (off-lattice) native-centric Gō-like models with a coarse-grained C$_α$ chain representation. We study a series of models in which the (local) bond- and torsion-angle terms have different strengths relative to the (nonlocal) pairwise contact energy terms. Conformational distributions in these models are sampled by Langevin dynamics. Thermodynamic cooperativity is characterized by the experimental criteria requiring the van't Hoff to calorimetric enthalpy ratio $ΔH_{\rm vH}/ΔH_{\rm cal}\approx 1$ (the calorimetric criterion), as well as a two-state-like variation of the average radius of gyration upon denaturation. We find that both local and nonlocal interactions are critical for thermodynamic cooperativity. Chain models with either much weakened local conformational propensities or much weakened favorable nonlocal interactions are significantly less cooperative than chain models with both strong local propensities and strong favorable nonlocal interactions. These findings are compared with results from a recently proposed lattice model with a local-nonlocal coupling mechanism; their relationship with experimental measurements of protein cooperativity and chain compactness is discussed.

cond-mat.stat-mech↗

arXiv2003

Origins of Chevron Rollovers in Non-Two-State Protein Folding Kinetics

Chevron rollovers of some proteins imply that their logarithmic folding rates are nonlinear in native stability. This is predicted by lattice and continuum Gō models to arise from diminished accessibilities of the ground state from transiently populated compact conformations under strongly native conditions. Despite these models' native-centric interactions, the slowdown is due partly to kinetic trapping caused by some of the folding intermediates' nonnative topologies. Notably, simple two-state folding kinetics of small single-domain proteins are not reproduced by common Gō-like schemes.

cond-mat.soft↗

arXiv2003

Contact Order Dependent Protein Folding Rates: Kinetic Consequences of a Cooperative Interplay Between Favorable Nonlocal Interactions and Local Conformational Preferences

Physical mechanisms underlying the empirical correlation between relative contact order (CO) and folding rate among naturally-occurring small single-domain proteins are investigated by evaluating postulated interaction schemes for a set of three-dimensional 27mer lattice protein models with 97 different CO values. Many-body interactions are constructed such that contact energies become more favorable when short chain segments sequentially adjacent to the contacting residues adopt native-like conformations. At a given interaction strength, this scheme leads to folding rates that are logarithmically well correlated with CO (correlation coefficient $r=0.914$) and span more than 2.5 orders of magnitude, whereas folding rates of the corresponding Gō models with additive contact energies have much less logarithmic correlation with CO and span only approximately one order of magnitude. The present protein chain models also exhibit calorimetric cooperativity and linear chevron plots similar to that observed experimentally for proteins with apparent simple two-state folding/unfolding kinetics. Thus, our findings suggest that CO-dependent folding rates of real proteins may arise partly from a significant positive coupling between nonlocal contact favorabilities and local conformational preferences.

cond-mat.stat-mech↗

arXiv2002

Solvation Effects and Driving Forces for Protein Thermodynamic And Kinetic Cooperativity: How Adequate Is Native-Centric Topological Modeling?

What energetic and solvation effects underlie the remarkable two-state thermodynamics and folding/unfolding kinetics of small single-domain proteins? To address this question, we investigate the folding and unfolding of a hierarchy of continuum Langevin dynamics models of chymotrypsin inhibitor 2. We find that residue-based additive Gō-like contact energies, although native-centric, are by themselves insufficient for proteinlike calorimetric two-state cooperativity. Further native biases by local conformational preferences are necessary for proteinlike thermodynamics. Kinetically, however, even models with both contact and local native-centric energies do not produce simple two-state chevron plots. Thus a model protein's thermodynamic cooperativity is not sufficient for simple two-state kinetics. The models tested appear to have increasing internal friction with increasing native stability, leading to chevron rollovers that typify kinetics that are commonly referred to as non-two-state. The free energy profiles of these models are found to be sensitive to the choice of native contacts and the presumed spatial ranges of the contact interactions. Motivated by explicit-water considerations, we explore recent treatments of solvent granularity that incorporate desolvation free energy barriers into effective implicit-solvent intraprotein interactions. This additional feature reduces both folding and unfolding rates vis-à-vis that of the corresponding models without desolvation barriers, but the kinetics remain non-two-state. Taken together, our observations suggest that interaction mechanisms

cond-mat.stat-mech↗

arXiv2002

Towards A Consistent Modeling Of Protein Thermodynamic And Kinetic Cooperativity: How Applicable Is The Transition State Picture To Folding and Unfolding?

To what extent do general features of folding/unfolding kinetics of small globular proteins follow from their thermodynamic properties? To address this question, we investigate a new simplifed protein chain model that embodies a cooperative interplay between local conformational preferences and hydrophobic burial. The present four-helix-bundle 55mer model exhibits proteinlike calorimetric two-state cooperativity. It rationalizes native-state hydrogen exchange observations. Our analysis indicates that a coherent, self-consistent physical account of both the thermodynamic and kinetic properties of the model leads naturally to the concept of a native state ensemble that encompasses considerable confomational fluctuations. Such a multiple-conformation native state is seen to involve conformational states similar to those revealed by native-state hydrogen exchange. Many of these conformational states are predicted to lie below native baselines commonly used in interpreting calorimetric data. Folding and unfolding kinetics are studied under a range of intrachain interaction strengths as in experimental chevron plots. Kinetically determined transition midpoints match well with their thermodynamic counterparts. Kinetic relaxations are found to be essentially single exponential over an extended range of model interaction strengths. This includes the entire unfolding regime and a significant part of a folding regime with ...

cond-mat.soft↗

arXiv2000

Energetic Components of Cooperative Protein Folding

A new lattice protein model with a four-helix bundle ground state is analyzed by a parameter-space Monte Carlo histogram technique to evaluate the effects of an extensive variety of model potentials on folding thermodynamics. Cooperative helical formation and contact energies based on a 5-letter alphabet are found to be insufficient to satisfy calorimetric and other experimental criteria for two-state folding. Such proteinlike behaviors are predicted, however, by models with polypeptide-like local conformational restrictions and environment-dependent hydrogen bonding-like interactions.

cond-mat.stat-mech↗

arXiv2000

Polymer Principles of Protein Calorimetric Two-State Cooperativity

The experimental calorimetric two-state criterion requires the van't Hoff enthalpy $ΔH_{\rm vH}$ around the folding/unfolding transition midpoint to be equal or very close to the calorimetric enthalpy $ΔH_{\rm cal}$ of the entire transition. We use an analytical model with experimental parameters from chymotrypsin inhibitor 2 to elucidate the relationship among several different van't Hoff enthalpies used in calorimetric analyses. Under reasonable assumptions, the implications of these $ΔH_{\rm vH}$'s being approximately equal to $ΔH_{\rm cal}$ are equivalent: Enthalpic variations among denatured conformations in real proteins are much narrower than some previous lattice-model estimates, suggesting that the energy landscape theory ``folding to glass transition temperature ratio'' $T_{\rm f}/T_{\rm g}$ may exceed 6.0 for real calorimetrically two-state proteins. Several popular three-dimensional lattice protein models, with different numbers of residue types in their alphabets, are found to fall short of the high experimental standard for being calorimetrically two-state. Some models postulate a multiple-conformation native state with substantial pre-denaturational energetic fluctuations well below the unfolding transition temperature and/or predict a significant post-denaturational continuous conformational expansion of the denatured ensemble at temperatures well above the transition point.

cond-mat.stat-mech↗