Biology subjects

de Vink, P. J.

Publications and source records attributed to de Vink, P. J..

2 recordsLinked to original sources

bioRxiv2022

Early identification of cooperative fragments for protein-protein interaction stabilization

Modulating protein-protein interactions (PPIs) is an effective approach to drug discovery, with several drugs in the clinic that inhibit PPIs. The orthogonal approach of PPI stabilization has developed slowly, a function of the complicated dynamics of multi-component protein complexes. In contrast to PPI inhibition, where ligand affinity is the driving parameter for efficacy, cooperativity is frequently the directing variable for PPI stabilization. Here we show how STD NMR allows for early-stage detection of cooperativity using the hub protein 14-3-3, a focused library of fragments and several 14-3-3 partner proteins. Further, we validate that the observed enhancement in STD signal is a function of cooperativity of the ternary 14-3-3 complex, using mutagenesis and X-ray crystallography. Additionally, we assess the differential cooperativity of three fragments in a panel of 14-3-3 interaction partners. Finally, we demonstrate how selective 14-3-3 complex formation is a function of cooperativity effects

biochemistry↗

bioRxiv2021

A general framework for straightforward model construction of multi-component thermodynamic equilibrium systems

Mathematical modelling of molecular systems helps elucidating complex phenomena in (bio)chemistry. However, equilibrium conditions in systems consisting of more than two components can typically not be analytically determined without assumptions and resulting (semi-)numerical models are not trivial to derive by the non-expert. Here we present a framework for equilibrium models that utilizes a general derivation method capable of generating custom models for complex molecular systems, based on the simple, reversible reactions describing these systems. Several molecular systems are revisited via the framework and demonstrate the simplicity, the generality and validity of the approach. The ease of use of the framework and the ability to both analyze systems and gain additional insights in the underlying parameters strongly aids the analysis and understanding of molecular equilibrium systems. This conceptual framework severely reduces the time and expertise requirements which currently impede the broad integration of these highly valuable models into chemical research.

biochemistry↗