Dr. Jianhan Chen
University of Massachusetts, Amherst
Hosted by: Dr. Davit Potoyan
Towards accurate simulation of coupling between protein secondary structure and phase separation
Intrinsically disordered proteins (IDPs) frequently mediate phase separation that underlies the formation of bimolecular condensates, which are believed to be involved in numerous biological processes and attracted intense attentions in recent years. Together with theory and experiment, efficient coarse-grained simulations have been instrumental in understanding sequence-specific phase separation of IDPs. However, the widely-used CA-only models are severely limited in capturing the peptide nature of IDPs, including backbone-mediated interactions and transient secondary structures. Here, we describe a hybrid resolution (HyRes) protein model for accurate description of the backbone and transient secondary structures in phase separation. With an atomistic backbone and coarse-grained side chains, HyRes accurately predicts the residue helical propensity and chain dimension of monomeric IDPs. Using GY-23 as a model system, we show that HyRes is efficient enough for direct simulation of spontaneous phase separation, and at the same time accurate enough to resolve the effects of single mutations. HyRes simulations also successfully predict increased beta-sheet formation in the condensate, consistent with available experimental data. We further utilize HyRes to study the phase separation of TPD-43, where several disease-related mutants in the conserved region (CR) have been shown to affect residual helicity and modulate condensate stability. The simulations successfully recapitulate the effect of these mutants on the helicity and phase separation propensity of TDP-43 CR. Analyses reveal that the balance between backbone and side chain-mediated interactions, but not helicity itself, actually determines phase separation propensity. We believe that the HyRes model represents an important advance in the molecular simulation of IDP phase separation and will help elucidate the coupling between transient secondary structures and phase separation.
Jianhan Chen is currently a Professor in the Department of Chemistry and Institute for Applied Life Sciences at University of Massachusetts, Amherst. His research program focuses on the development of theoretical and computational methods and application of these methods to advance our understanding of biophysical, biochemical and biomedical problems. Key problems currently under study in Dr. Chen’s lab include intrinsically disordered proteins in biology and diseases, protein amyloid formation in neurogenerative diseases, self-assembling peptide vesicles for drug delivery, protein nanopore tweezers, and transmembrane ion channel protein activation and regulation. Dr. Chen is a recipient of the NSF Career Award (2010), ACS Outstanding Junior Faculty Award (2011), multiple Innovative Research Awards from Kansas State University, and an Outstanding Research Award in Research from UMass (2022). He received his BS in Chemistry from the University of Science and Technology of China in 1998, PhD in Chemical and Materials Physics from the University of California at Irvine in 2002, and postdoctoral training with Charles L. Brooks III and Peter Wright at the Scripps Research Institute from 2002 to 2007.