Molecular simulations integrated with experiments for probing the interaction dynamics and binding mechanisms of intrinsically disordered proteins.

Intrinsically disordered proteins (IDPs) exploit their plasticity to deploy a rich panoply of soft interactions and binding phenomena. Advances in tailoring molecular simulations for IDPs combined with experimental cross-validation offer an atomistic view of the mechanisms that control IDP binding, function, and dysfunction. The emerging theme is that unbound IDPs autonomously form transient local structures and self-interactions that determine their binding behavior.

Insights into next generation sequencing guided antibody selection strategies.

Therapeutic antibody discovery often relies on in-vitro display methods to identify lead candidates. Assessing selected output diversity traditionally involves random colony picking and Sanger sequencing, which has limitations. Next-generation sequencing (NGS) offers a cost-effective solution with increased read depth, allowing a comprehensive understanding of diversity.

A modular approach to map out the conformational landscapes of unbound intrinsically disordered proteins.

Intrinsically disordered proteins (IDPs) fold upon binding to select/recruit multiple partners, morph around the partner's structure, and exhibit allostery. However, we do not know whether these properties emerge passively from disorder, or rather are encoded into the IDP's folding mechanisms. A main reason for this gap is the lack of suitable methods to dissect the energetics of IDP conformational landscapes without partners.

Molecular Simulations of Intrinsically Disordered Proteins and Their Binding Mechanisms.

Intrinsically disordered proteins (IDPs) lack well-defined secondary or tertiary structures in solution but are found to be involved in a wide range of critical cellular processes that highlight their functional importance. IDPs usually undergo folding upon binding to their targets. Such binding coupled to folding behavior has widened our perspective on the protein structure-dynamics-function paradigm in molecular biology.

Downhill (Un)Folding Coupled to Binding as a Mechanism for Engineering Broadband Protein Conformational Transducers.

Canonical proteins fold and function as conformational switches that toggle between their folded (on) and unfolded (off) states, a mechanism that also provides the basis for engineering transducers for biosensor applications. One of the limitations of such transducers, however, is their relatively narrow operational range, limited to ligand concentrations 20-fold below or above their C. Previously, we discovered that certain fast-folding proteins lose/gain structure gradually (downhill folding), which led us to postulate their operation as conformational rheostats capable of processing inputs/outputs in analog fashion.

Glutton: a tool for generating structural ensembles of partly disordered proteins from chemical shifts.

Motivation: Many proteins are partially disordered in physiological conditions and only fold, fully or partially, upon binding. Their structural analysis is challenging because the accessible information, typically chemical shifts (CS) from nuclear magnetic resonance experiments, are averages over broad ensembles of conformations. We aim to develop a database for the analysis of such data in terms of conformational distributions of the protein backbone rather than of individual high-resolution structures.

Decoding Structural Properties of a Partially Unfolded Protein Substrate: En Route to Chaperone Binding.

Many proteins comprising of complex topologies require molecular chaperones to achieve their unique three-dimensional folded structure. The E.coli chaperone, GroEL binds with a large number of unfolded and partially folded proteins, to facilitate proper folding and prevent misfolding and aggregation.