Track topics on Twitter Track topics that are important to you
Intrinsically disordered proteins (IDPs) exert their functions by binding to partner proteins via a complex process that includes coupled folding and binding. Motivated by that inhibiting the binding of the IDP p53 to its partner MDM2 has become a promising strategy for the design of anticancer drugs, we carried out metadynamics simulations to study the coupled folding and binding process linking the IDP p53 to MDM2 in atomic detail. Using bias-exchange metadynamics (BE-MetaD) and infrequent metadynamics (InMetaD) we estimated the binding free energy, the unbinding rate and the binding rate. By analyzing the stable intermediates, we uncovered the role of nonnative interactions played in the p53-MDM2 binding/unbinding process. We used a three-state model to describe the whole binding/unbinding process and to obtain the corresponding rate constants. Our work shows that the binding of p53 favors an induced fit mechanism which proceeds in a stepwise fashion. Our results can be helpful for the in-depth understanding of the coupled folding and binding process needed for the design of MDM2 inhibitors.
This article was published in the following journal.
Name: Journal of chemical information and modeling
Intrinsically Disordered Proteins (IDPs) are a class of protein that exert their function despite lacking a well-defined three-dimensional structure, which is sometimes achieved only upon binding to t...
Intrinsically disordered protein regions may fold upon binding to an interaction partner. It is often argued that such coupled binding and folding enables the combination of high specificity with low ...
The abundance of protein dimers and multidomain proteins is a testimony to their importance in various cellular functions. Several mechanisms exist, explaining how they assemble. The energy landscape ...
Confined hydration and conformational flexibility are some of the challenges encountered for the rational design of selective antagonists of G-protein coupled receptors. We present a set of C3-substit...
Measuring binding between molecules is critical for understanding basic biochemical processes, developing molecular diagnosis, and screening drugs. Here we study molecular binding at the single molecu...
The aim of this research is to assess the acceptability of using a mobile folding screen for blinding parents of infant study participants in clinical trials of osteopathic interventions. ...
Intraabdominal fungal infections with Candida are constantly increasing. Their diagnosis and treatment is difficult. Morbidity and mortality are high. Β-D-Glucan has been proposed as a ma...
The present study was based on secondary analysis using the non-intervention control conditions of five separate studies with common measures. The current analysis examine the indirect and...
Infertility affects an increasing number of couples. For many, the choice of treatment is in vitro fertilization (IVF) . Currently, there are no markers fully predictive of developmental c...
According to the free hormone hypothesis, the biological activity of a hormone is carried by the portion that is not bound to protein or its carrier in circulation. Based on this, we belie...
Electron transfer through the cytochrome system liberating free energy which is transformed into high-energy phosphate bonds.
GTP-BINDING PROTEINS that contain three non-identical subunits. They are found associated with members of the seven transmembrane domain superfamily of G-PROTEIN-COUPLED RECEPTORS. Upon activation the GTP-BINDING PROTEIN ALPHA SUBUNIT of the complex dissociates leaving a dimer of a GTP-BINDING PROTEIN BETA SUBUNIT bound to a GTP-BINDING PROTEIN GAMMA SUBUNIT.
Proteins that catalyze the unwinding of duplex DNA during replication by binding cooperatively to single-stranded regions of DNA or to short regions of duplex DNA that are undergoing transient opening. In addition DNA helicases are DNA-dependent ATPases that harness the free energy of ATP hydrolysis to translocate of DNA strands.
Electric power supply devices which convert biological energy, such as chemical energy of metabolism or mechanical energy of periodic movements, into electrical energy.
An ATP-binding cassette, sub-family B protein (ATP BINDING CASSETTE TRANSPORTER, SUB-FAMILY B) that functions in the transport of ANTIGENS from the CYTOPLASM to the ENDOPLASMIC RETICULUM for association with HISTOCOMPATIBILITY ANTIGENS CLASS I peptides. It also acts as a molecular scaffold for the final stage of MHC class I PROTEIN FOLDING.
Within medicine, nutrition (the study of food and the effect of its components on the body) has many different roles. Appropriate nutrition can help prevent certain diseases, or treat others. In critically ill patients, artificial feeding by tubes need t...
Collaborations in biotechnology
Commercial and academic collaborations are used throughout the biotechnology and pharmaceutical sector to enhance research and product development. Collaborations can take the form of research and evaluation agreements, licensing, partnerships etc. ...