Intrinsically Disordered Proteins (IDPs) perform a broad range of biological functions. Their relevance has motivated intense research activity seeking to characterize their sequence/structure/function relationships. However, the conformational plasticity of these molecules hampers the application of traditional structural approaches, and new tools and concepts are being developed to address the challenges they pose. Small-Angle Scattering (SAS) is a structural biology technique that probes the size and shape of disordered proteins and their complexes with other biomolecules. The low-resolution nature of SAS can be compensated with specially designed computational tools and its combined interpretation with complementary structural information. In this review, we describe recent advances in the application of SAS to disordered proteins and highly flexible complexes and discuss current challenges.
Many pairwise additive force fields are in active use for intrinsically disordered proteins (IDPs) and regions (IDRs), some of which modify energetic terms to improve description of IDPs/IDRs, but are largely in disagreement with solution experiments for the disordered states. We have evaluated representative pairwise and many-body protein and water force fields against experimental data on representative IDPs and IDRs, a peptide that undergoes a disorder-to-order transition, and for seven globular proteins ranging in size from 130-266 amino acids. We find that force fields with the largest st…
A significant part of the proteome is composed of intrinsically-disordered proteins (IDPs). These proteins do not fold into a well-defined structure and behave like ordinary polymers. In this work we consider IDPs which have the tendency to aggregate, model them as heteropolymers that contain a small number of associating monomers and use computer simulations in order to compare the aggregation of such IDPs that are grafted to a surface or free in solution. We then discuss how such grafting may affect the analysis of in-vitro experiments and could also be used to suppress harmful aggregation.
Intrinsically disordered proteins (IDPs) do not possess well-defined three-dimensional structures in solution under physiological conditions. We develop all-atom, united-atom, and coarse-grained Langevin dynamics simulations for the IDP alpha-synuclein that include geometric, attractive hydrophobic, and screened electrostatic interactions and are calibrated to the inter-residue separations measured in recent smFRET experiments. We find that alpha-synuclein is disordered with conformational statistics that are intermediate between random walk and collapsed globule behavior. An advantage of cali…
Glassy, nonexponential relaxations in globular proteins are typically attributed to conformational behaviors that are missing from intrinsically disordered proteins. Yet, we show that single molecules of a disordered-protein construct display two signatures of glassy dynamics, logarithmic relaxations and a Kovacs memory effect, in response to changes in applied tension. We attribute this to the presence of multiple independent local structures in the chain, which we corroborate with a model that correctly predicts the force dependence of the relaxation. The mechanism established here likely ap…
The human proteome is enriched in proteins that do not fold into a stable 3D structure. These intrinsically disordered proteins (IDPs) spontaneously fluctuate between a large number of configurations in their native form. Remarkably, the disorder does not lead to dysfunction as with denatured folded proteins. In fact, unlike denatured proteins, recent evidences strongly suggest that multiple biological functions stem from such structural plasticity. Here, focusing on the nanoscopic length-scale, we review the latest advances in IDP research and discuss some of the future directions in this hig…
Curvature-inducing proteins containing a Bin/Amphiphysin/Rvs domain often have intrinsically disordered domains. Recent experiments have shown that these disordered chains enhance curvature sensing and generation. Here, we report on the modification of protein-membrane interactions by disordered chains using meshless membrane simulations. The protein and bound membrane are modeled together as a chiral crescent protein rod with two excluded-volume chains. As the chain length increases, the repulsion between them reduces the cluster size of the proteins. It induces spindle-shaped vesicles and a …
The biological function of protein assemblies was conventionally equated with a unique three-dimensional protein structure and protein-specific interactions. However, in the past 20 years it was found that some assemblies contain long flexible regions that adopt multiple structural conformations. These include neurofilament (NF) proteins that constitute the stress-responsive supportive network of neurons. Herein, we show that NF networks macroscopic properties are tuned by enzymatic regulation of the charge found on the flexible protein regions. The results reveal an enzymatic (phosphorylation…
Amphiphilic molecules and their self-assembled structures have long been the target of extensive research due to their potential applications in fields ranging from materials design to biomedical and cosmetic applications. Increasing demands for functional complexity have been met with challenges in biochemical engineering, driving researchers to innovate in the design of new amphiphiles. An emerging class of molecules, namely, peptide amphiphiles, combines key advantages and circumvents some of the disadvantages of conventional phospholipids and block-copolymers. Herein, we present new peptid…
From isolated polyelectrolytes to star-like assemblies: The role of sequence heterogeneity on the statistical structure of the intrinsically disordered Neurofilament-low tail domain
A general approach for calculating spectral and optical properties of pigment-protein complexes of known atomic structure is presented. The method, that combines molecular dynamics simulations, quantum chemistry calculations and statistical mechanical modeling, is demonstrated by calculating the absorption and circular dichroism spectra of the B800-B850 BChls of the LH2 antenna complex from Rs. molischianum at room temperature. The calculated spectra are found to be in good agreement with the available experimental results. The calculations reveal that the broadening of the B800 band is mainly…
The paradigm that the primary amino acid sequence prescribes structure and thus function has for a long time been central to the understanding of protein science. Though the theory is supported by the behaviour of most structured proteins, it loses much of its applicability when discussing intrinsically disordered proteins (IDPs). These peculiar proteins, whose tertiary structure constantly interconverts between a series of energetically favourable conformations, are the root of many current, pressing scientific mechanisms. Many biological processes that are still yet to be elucidated--the mec…
Disordered quantum networks, as those describing light-harvesting complexes, are often characterized by the presence of antenna structures where the light is captured and inner structures (reaction centers) where the excitation is transferred. Antennae often display distinguished coherent features: their eigenstates can be separated, with respect to the transfer of excitation, in the two classes of superradiant and subradiant states. Both are important to optimize transfer efficiency. In absence of disorder superradiant states have an enhanced coupling strength to the RC, while subradiant ones…
Weak interactions form the core basis of a vast number of biological processes, in particular, those involving intrinsically disordered proteins. Here, we establish a new technique capable of probing these weak interactions between synthetic unfolded polypeptides using a convenient yet efficient, quantitative method based on single particle tracking of peptide-coated gold nanoparticles over peptide-coated surfaces. We demonstrate that our technique is sensitive enough to observe the influence of a single amino acid mutation on the transient peptide-peptide interactions. Furthermore, the effect…
The idea that structural disorder might be a novel mechanism of protein interaction is widespread in the Literature, although the number of statistically significant structural studies supporting this is surprisingly low. At variance with previous works, our conclusions rely exclusively on a large-scale analysis of all the 134337 X-ray crystallographic structures of the Protein Data Bank averaged over clusters of almost identical protein sequences. In this work, we explore the complexity of the organization of all the interaction interfaces observed when a protein lies in alternative complexes…
It is becoming clear that traditional, single-structure models of proteins are insufficient for understanding their biological function. Here, we outline one method for inferring, from experiments, not only the most common structure a protein adopts (native state), but the entire ensemble of conformations the system can adopt. Such ensemble mod- els are necessary to understand intrinsically disordered proteins, enzyme catalysis, and signaling. We suggest that the most difficult aspect of generating such a model will be finding a small set of configurations to accurately model structural hetero…
Abeta is a disordered peptide central to Alzheimer's Disease. Aggregation of Abeta has been widely explored, but its molecular crowding less so. The synaptic cleft where Abeta locates only holds 60-70 water molecules along its width. We subjected Abeta40 to 100 different simulations with variable water cell size. We show that even for this disordered aggregation-prone peptide, many properties are not cell-size dependent, i.e. a small cell is easily justified. The radius of gyration, intra-peptide, and peptide-water hydrogen bonds are well-sampled by short (50 ns) time scales at any cell size. …
We use a coarse-grained molecular model to study the self-assembly process of complexes of cationic and neutral lipids with DNA molecules ("lipoplexes") - a promising nonviral carrier of DNA for gene therapy. We identify the resulting structures through direct visualization of the molecular arrangements and through calculations of the corresponding scattering plots. The latter approach provides a means for comparison with published data from X-ray scattering experiments. Consistent with experimental results, we find that upon increasing the stiffness of the lipid material, the system tends to …
NANOG assembles into self-limiting aging micelles that drive a sol-gel transition and modulate DNA dynamics
Centre for Regenerative Medicine, Institute for Regeneration and Repair（再生医学中心，再生与修复研究所）；School of Physics and Astronomy, University of Edinburgh（爱丁堡大学物理与天文学院）；School of Molecular Biosciences, University of Glasgow（格拉斯哥大学生物分子科学学院）；Institute for Stem Cell Research, School of Biological Sciences, University of Edinburgh（爱丁堡大学生物科学学院干细胞研究所）
During the last decade, network approaches became a powerful tool to describe protein structure and dynamics. Here we review the links between disordered proteins and the associated networks, and describe the consequences of local, mesoscopic and global network disorder on changes in protein structure and dynamics. We introduce a new classification of protein networks into cumulus-type, i.e., those similar to puffy (white) clouds, and stratus-type, i.e., those similar to flat, dense (dark) low-lying clouds, and relate these network types to protein disorder dynamics and to differences in energ…
The photo-triggered unbinding of the intrinsically disordered S-peptide from the RNase S complex is studied with the help of transient IR spectroscopy, covering a wide range of time scales from 100 ps to 10 ms. To that end, an azobenzene moiety has been linked to the S-peptide in a way that its helicity is disrupted by light, thereby initiating its complete unbinding. The full sequence of events is observed, starting from unfolding of the helical structure of the S-peptide on a 20 ns timescale while still being in the binding pocket of the S-protein, S-peptide unbinding after 300 microseconds,…
Photosynthetic antenna complexes capture and concentrate solar radiation by transferring the excitation to the reaction center which stores energy from the photon in chemical bonds. This process occurs with near-perfect quantum efficiency. Recent experiments at cryogenic temperatures have revealed that coherent energy transfer - a wavelike transfer mechanism - occurs in many photosynthetic pigment-protein complexes (1-4). Using the Fenna-Matthews-Olson antenna complex (FMO) as a model system, theoretical studies incorporating both incoherent and coherent transfer as well as thermal dephasing p…
Eukaryotic cells intrinsically change their shape, by changing the composition of their membrane and by restructuring their underlying cytoskeleton. We present here further studies and extensions of a minimal physical model, describing a closed vesicle with mobile curved membrane protein complexes. The cytoskeletal forces describe the protrusive force due to actin polymerization which is recruited to the membrane by the curved protein complexes. We characterize the phase diagrams of this model, as function of the magnitude of the active forces, nearest-neighbor protein interactions and the pro…
