Drugging Fuzzy Complexes in Transcription

Transcription factors (TFs) are one of the most promising but underutilized classes of drug targets. The high degree of intrinsic disorder in both the structure and the interactions (i.e., “fuzziness”) of TFs is one of the most important challenges to be addressed in this context. Here, we discuss the impacts of fuzziness on transcription factor drug discovery, describing how disorder poses fundamental problems to the typical drug design, and screening approaches used for other classes of proteins such as receptors or enzymes. We then speculate on ways modern biophysical and chemical biology approaches could synergize to overcome many of these challenges by directly addressing the challenges imposed by TF disorder and fuzziness.

Uniformly Frustrated XY Model: Strengthening of the Vortex Lattice by Intrinsic Disorder

In superconducting films, the role of intrinsic disorder is typically to compete with superconductivity by fragmenting the global phase coherence and lowering the superfluid density. Nonetheless, when a transverse magnetic field is applied to the system and an Abrikosov vortex lattice form, the presence of disorder can actually strengthen the superconducting state against thermal fluctuations. By means of Monte Carlo simulations on the uniformly frustrated XY model in two dimensions, we show that while for weak pinning the superconducting critical temperature Tc increases with the applied field H, for strong enough pinning, the experimental decreasing dependence between Tc and H is recovered with a resulting more robust vortex lattice.

Role of “dual-personality” fragments in HEV adaptation—analysis of Y-domain region

Background Hepatitis E is a liver disease caused by the pathogen hepatitis E virus (HEV). The largest polyprotein open reading frame 1 (ORF1) contains a nonstructural Y-domain region (YDR) whose activity in HEV adaptation remains uncharted. The specific role of disordered regions in several nonstructural proteins has been demonstrated to participate in the multiplication and multiple regulatory functions of the viruses. Thus, intrinsic disorder of YDR including its structural and functional annotation was comprehensively studied by exploiting computational methodologies to delineate its role in viral adaptation. Results Based on our findings, it was evident that YDR contains significantly higher levels of ordered regions with less prevalence of disordered residues. Sequence-based analysis of YDR revealed it as a “dual personality” (DP) protein due to the presence of both structured and unstructured (intrinsically disordered) regions. The evolution of YDR was shaped by pressures that lead towards predominance of both disordered and regularly folded amino acids (Ala, Arg, Gly, Ile, Leu, Phe, Pro, Ser, Tyr, Val). Additionally, the predominance of characteristic DP residues (Thr, Arg, Gly, and Pro) further showed the order as well as disorder characteristic possessed by YDR. The intrinsic disorder propensity analysis of YDR revealed it as a moderately disordered protein. All the YDR sequences consisted of molecular recognition features (MoRFs), i.e., intrinsic disorder-based protein–protein interaction (PPI) sites, in addition to several nucleotide-binding sites. Thus, the presence of molecular recognition (PPI, RNA binding, and DNA binding) signifies the YDR’s interaction with specific partners, host membranes leading to further viral infection. The presence of various disordered-based phosphorylation sites further signifies the role of YDR in various biological processes. Furthermore, functional annotation of YDR revealed it as a multifunctional-associated protein, due to its susceptibility in binding to a wide range of ligands and involvement in various catalytic activities. Conclusions As DP are targets for regulation, thus, YDR contributes to cellular signaling processes through PPIs. As YDR is incompletely understood, therefore, our data on disorder-based function could help in better understanding its associated functions. Collectively, our novel data from this comprehensive investigation is the first attempt to delineate YDR role in the regulation and pathogenesis of HEV.

Per aspera ad chaos: a personal journey to the wonderland of intrinsic disorder

This perspective article describes some of the key points of my personal journey through the intriguing world of intrinsically disordered proteins (IDPs). It also shows the evolution of my perception of functional proteins from a standard lock-and-key theory, where a unique function is defined by a unique 3D structure, to the structure–function continuum model, where the structural heterogeneity and conformational plasticity of IDPs define their remarkable multifunctionality and binding promiscuity. These personal accounts of the difficult and lengthy transition from order to disorder paralleled the uneasy and challenging transition in the mind of the scientific community from disbelief in intrinsic disorder to acceptance of IDPs as real entities that play critical biological roles. I hope that this perspective will be of interest to the readers of this journal.