Some frequently encountered deficiencies in all-atom molecular simulations, such as nonspecific protein–protein interactions being too strong, and unfolded or disordered states collapsed, suggest that proteins are insufficiently well solvated simulations using current state-of-the-art force fields. To address these issues, we make the simplest possible change, by modifying short-range protein–water pair interactions, leaving all water–water parameters unchanged. We find a modest...

Article8 August 2017Open Access Transparent process Phosphorylation of the FUS low-complexity domain disrupts phase separation, aggregation, and toxicity Zachary Monahan Department Pharmacology Molecular Therapeutics, Uniformed Services University, Bethesda, MD, USA Search for more papers by this author Veronica H Ryan Neuroscience Graduate Program, Brown Providence, RI, Abigail M Janke Pharmacology, Physiology, Biotechnology, Kathleen A Burke Shannon N Rhoads Gül Zerze Chemical Biomolecular...

Membraneless organelles important to intracellular compartmentalization have recently been shown comprise assemblies of proteins which undergo liquid-liquid phase separation (LLPS). However, many involved in this are at least partially disordered. The molecular mechanism and the sequence determinants process challenging determine experimentally owing disordered nature assemblies, motivating use theoretical simulation methods. This work advances a computational framework for conducting...

Proteins that undergo liquid-liquid phase separation (LLPS) have been shown to play a critical role in many physiological functions through formation of condensed liquid-like assemblies function as membraneless organelles within biological systems. To understand how different proteins may contribute differently these and their functions, it is important the molecular driving forces characterize boundaries material properties. Experimental studies intrinsically disordered regions are major...

We present a multiscale method for the determination of collective reaction coordinates macromolecular dynamics based on two recently developed mathematical techniques: diffusion map and local intrinsic dimensionality large datasets. Our accounts variation molecular configuration space, resulting global are correlated with time scales motion. To illustrate approach, we results model systems: all-atom alanine dipeptide coarse-grained src homology 3 protein domain. provide clear physical...

The liquid-liquid phase separation (LLPS) of intrinsically disordered proteins (IDPs) is a commonly observed phenomenon within the cell, and such condensates are also highly attractive for applications in biomaterials drug delivery. A better understanding sequence-dependent thermoresponsive behavior immense interest as it will aid design protein sequences with desirable properties cellular response to heat stress. In this work, we use transferable coarse-grained model directly probe IDPs. To...

The long-timescale dynamics of macromolecular systems can be oftentimes viewed as a reaction connecting metastable states the system. In past decade, various approaches have been developed to discover collective motions associated with this dynamics. corresponding variables are used in many applications, e.g., understand mechanism, quantify system's free energy landscape, enhance sampling path, and determine rate. review we focus on number key developments field, providing an overview...

The formation of membraneless organelles in cells commonly occurs via liquid-liquid phase separation (LLPS) and is many cases driven by multivalent interactions between intrinsically disordered proteins (IDPs). Investigating the nature these interactions, their effect on dynamics within condensed phase, therefore critical importance but very challenging for either simulation or experiment. Here, we study pairing a novel multiscale strategy with microsecond all-atom MD simulations condensed,...

There has been a long-standing controversy regarding the effect of chemical denaturants on dimensions unfolded and intrinsically disordered proteins: A wide range experimental techniques suggest that polypeptide chains expand with increasing denaturant concentration, but several studies using small-angle X-ray scattering (SAXS) have reported no such increase radius gyration (Rg). This inconsistency challenges our current understanding mechanism denaturants, which are widely employed to...

A nanoparticle-conjugated cancer drug provides a novel strategy for therapy. In this study, we manipulated nanodiamond (ND), carbon nanomaterial, to covalently link paclitaxel delivery and Paclitaxel was bound the surface of 3–5 nm sized ND through succession chemical modifications. The ND-paclitaxel conjugation measured by atomic force microscope nuclear magnetic resonance spectroscopy, confirmed with infrared spectroscopy detection deuterated paclitaxel. Treatment 0.1–50 µg ml − 1 48 h...

Chemical denaturants are the most commonly used agents for unfolding proteins and thought to act by better solvating unfolded state. Improved solvation is expected lead an expansion of chains with increasing denaturant concentration, providing a sensitive probe action. However, experiments have so far yielded qualitatively different results concerning effects chemical denaturation. Studies using Förster resonance energy transfer (FRET) other methods found increase in radius gyration but...

Abstract Ribonucleoprotein (RNP) granules are membraneless organelles (MLOs), which majorly consist of RNA and RNA-binding proteins formed via liquid–liquid phase separation (LLPS). Experimental studies investigating the drivers LLPS have shown that intrinsically disordered (IDPs) nucleic acids like other polynucleotides play a key role in modulating protein separation. There is currently dearth modelling techniques allow one to delve deeper into how modulator/promoter cells using...

Understanding the conformational ensemble of an intrinsically disordered protein (IDP) is great interest due to its relevance critical intracellular functions and diseases. It now well established that polymer scaling behavior can provide a deal information about properties as liquid–liquid phase separation IDP. is, therefore, extremely desirable be able predict IDP's from sequence itself. The work in this direction so far has focused on highly charged proteins how charge patterning perturb...

Förster resonance energy transfer (FRET) is a powerful tool for elucidating both structural and dynamic properties of unfolded or disordered biomolecules, especially in single-molecule experiments. However, the key observables, namely, mean efficiency fluorescence lifetimes donor acceptor chromophores, are averaged over broad distribution donor-acceptor distances. The inferred average ensemble therefore depend on form model chosen to describe distance, as has been widely recognized. In...

Experimental studies on intrinsically disordered and unfolded proteins have shown that in isolation they typically low populations of secondary structure exhibit distance scalings suggesting are at near-theta-solvent conditions. Until recently, however, all-atom force fields failed to reproduce these fundamental properties (IDPs). Recent improvements by refining against ensemble-averaged experimental observables for polypeptides aqueous solution addressed deficiencies including bias, global...

This work describes the chemical modification of ultradispersed nanodiamond results in enrichment surface hydroxyl groups as by FT-IR, TGA, RGA-MS and XRD measurements. These can be conveniently functionalized with long chain alcohols (oxyhexanol) for easy manipulation different functional groups. The loading oxyhexanol were found to 0.13 mmol/g nanodiamond. functionalities on modified afford a new solid phase synthesis peptides facilitate covalent attachment drug molecules. conjugation...

The gap between the time scale of interesting behavior in macromolecular systems and that which our computational resources can afford often limits molecular dynamics (MD) from understanding experimental results predicting what is inaccessible experiments. In this paper, we introduce a new sampling scheme, named diffusion-map-directed MD (DM-d-MD), to rapidly explore configuration space. method uses diffusion map guide on fly. DM-d-MD be combined with other methods reconstruct equilibrium...

A recent study on the dynamics of polymer reversal inside a nanopore by Huang and Makarov [J. Chem. Phys. 128, 114903 (2008)]10.1063/1.2890006 demonstrated that reaction rate cannot be reproduced projecting onto single empirical coordinate, result suggesting this system correctly described using collective coordinate. To further investigate possibility we have applied our recently developed multiscale framework, locally scaled diffusion map (LSDMap), to obtain coordinates for system. Using...

Significance The ability to form large interaction networks was one of the driving forces in evolution disordered proteins. However, their advantageous flexibility is accompanied by a tremendous solvent sensitivity that does not seem have detrimental consequences. Our results provide possible explanation this conundrum. While individual interactions among 5 proteins are extremely sensitive, competition for shared ligands natural network largely compensates sensitivity. Recent ideas suggested...

The flexible structure of an intrinsically disordered protein (IDP) is known to be perturbed by salt concentrations, which can understood electrostatic screening on charged amino acids. However, IDP usually contains more uncharged residues that are influenced the salting-out effect. Here we have parametrized effect into a coarse-grained model using set Förster resonance energy transfer data and verified with experimental salt-dependent liquid–liquid phase separation (LLPS) 17 proteins. new...

Intrinsically disordered proteins often form dynamic complexes with their ligands. Yet, the speed and amplitude of these motions are hidden in classical binding kinetics. Here, we directly measure dynamics an exceptionally mobile, high-affinity complex. We show that tail cell adhesion protein E-cadherin dynamically samples a large surface area protooncogene β-catenin. Single-molecule experiments molecular simulations resolve high resolution space time. Contacts break within hundreds...