Seminars

Abstract

Structural biology studies over the last 50 years have provided an unprecedented view of structured domains, yet the structural details of a significant portion of the expressed proteome, characterized by IDRs, still remain in the dark. Research over the past decade has brought the functional significance of IDRs into the limelight. There are several established cases where disordered regions of a protein and IDPs transition to a structured state when they encounter a binding partner. Some of these interactions are weak, yet critical, dictated by need for a transient signal. Key cellular processes, including transcription and translation are orchestrated by many such interactions. The business end of transcription factors, the transactivation domain (TAD), is usually disordered and assume structure upon binding “helper” proteins such as co-activators and mediators to regulate transcription. The presentation will detail a structure-based approach to unravel the molecular details the interaction between the TAD and a Mediator subunit and use the information to target the interaction in two clinically relevant systems, affecting multiple drug resistance and lipogenesis.

Abstract

Protein folding research has been dominated by the assumption that thermodynamics determines protein structure and function. And that when the folding process is compromised in vivo the proteostasis machinery — chaperones, deaggregases, the proteasome — work to restore proteins to their soluble, functional form or degrade them to maintain the cellular pool of proteins in a quasi-equilibrium state. During the past decade, however, more and more proteins have been identified for which altering only their speed of synthesis alters their structure and function, the efficiency of the down-stream processes they take part in, and cellular phenotype. Indeed, evidence has emerged that evolutionary selection pressures have encoded translation-rate information into mRNA molecules to coordinate diverse co-translational processes. Thus, non-equilibrium physics can play a fundamental role in influencing nascent protein behavior, mRNA sequence evolution, and disease. In this talk I will discuss my lab's efforts to understand and model this phenomenon through the development application of theoretical tools from the physical sciences including coarse-grained simulations, chemical kinetics and statistical mechanics.

Abstract

Biological macromolecules function in dense, crowded cellular environments. Early studies of crowding effects have emphasized volume exclusion effects, but it is becoming clear that frequent non-specific interactions between proteins, nucleic acids, and metabolites may be the more important factor in modulating the structure and dynamics of biomolecules. Computer simulation studies at different scales of a series of models ranging from concentrated homogeneous protein solutions to models of bacterial cytoplasms are presented to explore the effects of non-specific quinary protein-protein interactions on protein stability and dynamics. One focus is on the formation of transient clusters that determine diffusive properties and lead to liquid-liquid phase transitions. The computational results are related to existing experimental data and the challenges and opportunities to expand the current studies to whole-cell modeling in molecular detail are discussed.