Search Results (3)

This comprehensive review examines FINCHES (Force field-based Interaction Network for Characterizing Heterotypic and Entropic Sequences). This groundbreaking computational framework enables the rapid, sequence-based prediction of intermolecular interactions in intrinsically disordered regions (IDRs) without the need for molecular simulations. The document provides detailed comparisons with other computational methods, including their mathematical foundations, specific applications, and experimental validations. We explore both the potential for advancing our understanding of disordered protein function and the inherent challenges in computationally modeling these dynamic biological systems. Additionally, we discuss computational assessment tools for interface prediction in molecular complexes, providing a comprehensive framework for evaluating IDR interaction predictions. Full article

A growing body of evidence suggests that only a few amino acids (“hot-spots”) at the interface contribute most of the binding energy in transient protein-protein interactions. However, experimental protocols to identify these hot-spots are highly labor-intensive and expensive. Computational methods, including evolutionary couplings, have been proposed to predict the hot-spots, but they generally fail to provide details of the interacting amino acids. Here we showed that unbiased evolutionary methods followed by biased molecular dynamic simulations could achieve this goal and reveal critical elements of protein complexes. We applied the methodology to selected G-protein coupled receptors (GPCRs), known for their therapeutic properties. We used the structure-prior-assisted direct coupling analysis (SP-DCA) to predict the binding interfaces of A2aR/D2R, CB1R/D2R, A2aR/CB1R, 5HT2AR/D2R, and 5-HT2AR/mGluR2 receptor heterodimers, which all agreed with published data. In order to highlight details of the interactions, we performed molecular dynamic (MD) simulations using the newly developed AWSEM energy model. We found that these receptors interact primarily through critical residues at the C and N terminal domains and the third intracellular loop (ICL3). The MD simulations showed that these residues are energetically necessary for dimerization and revealed their native conformational state. We subsequently applied the methodology to the 5-HT2AR/5-HTR4R heterodimer, given its implication in drug addiction and neurodegenerative pathologies such as Alzheimer’s disease (AD). Further, the SP-DCA analysis showed that 5-HT2AR and 5-HTR4R heterodimerize through the C-terminal domain of 5-HT2AR and ICL3 of 5-HT4R. However, elucidating the details of GPCR interactions would accelerate the discovery of druggable sites and improve our knowledge of the etiology of common diseases, including AD. Full article

Folded proteins show a high degree of structural order and undergo (fairly constrained) collective motions related to their functions. On the other hand, intrinsically disordered proteins (IDPs), while lacking a well-defined three-dimensional structure, do exhibit some structural and dynamical ordering, but are less constrained in their motions than folded proteins. The larger structural plasticity of IDPs emphasizes the importance of entropically driven motions. Many IDPs undergo function-related disorder-to-order transitions driven by their interaction with specific binding partners. As experimental techniques become more sensitive and become better integrated with computational simulations, we are beginning to see how the modest structural ordering and large amplitude collective motions of IDPs endow them with an ability to mediate multiple interactions with different partners in the cell. To illustrate these points, here, we use Prostate-associated gene 4 (PAGE4), an IDP implicated in prostate cancer (PCa) as an example. We first review our previous efforts using molecular dynamics simulations based on atomistic AWSEM to study the conformational dynamics of PAGE4 and how its motions change in its different physiologically relevant phosphorylated forms. Our simulations quantitatively reproduced experimental observations and revealed how structural and dynamical ordering are encoded in the sequence of PAGE4 and can be modulated by different extents of phosphorylation by the kinases HIPK1 and CLK2. This ordering is reflected in changing populations of certain secondary structural elements as well as in the regularity of its collective motions. These ordered features are directly correlated with the functional interactions of WT-PAGE4, HIPK1-PAGE4 and CLK2-PAGE4 with the AP-1 signaling axis. These interactions give rise to repeated transitions between (high HIPK1-PAGE4, low CLK2-PAGE4) and (low HIPK1-PAGE4, high CLK2-PAGE4) cell phenotypes, which possess differing sensitivities to the standard PCa therapies, such as androgen deprivation therapy (ADT). We argue that, although the structural plasticity of an IDP is important in promoting promiscuous interactions, the modulation of the structural ordering is important for sculpting its interactions so as to rewire with agility biomolecular interaction networks with significant functional consequences. Full article