Uncovering the molecular principles of intracellular electrochemistry

Biochemistry always requires an exact buffering environment (e.g., salt condition, pH). Considering the diversity of biochemical functions and spatial complexity of cellular processes in living cells, our lab is extremely curious about how living systems orchestrate the right buffering systems to satisfy diverse cellular functions in a spatial temporal manner and how these fundamental principles of life can be implemented to understand diseases and provide new tools for bioengineering. To address these questions, our lab works at the interface of physical chemistry and molecular and cell biology to 1) explore the fundamental physicochemical and electrochemical features of living systems, 2) establish a new theoretical framework to explore whether and to what extent these fundamental electrochemical features (e.g., proton motive force) can define passive chemical functions, 3) correlate the chemical and electrochemical environments with global cellular physiology to understand the developments of diseases and 4) design new fundamental capabilities for synthetic biology to study cellular behaviors and engineer cellular functions. Our recent works in biomolecular condensates have unveiled that macromolecular condensation can influence the electrochemical environment of the cytoplasm by modulating the distribution of solvent molecules between the dilute and the dense phases. The same process sets up an interfacial electric potential that defines an interfacial electric field at the surface of condensates, which can drive diverse chemical reactions. These recent discoveries shed light onto the longstanding mystery of intracellular buffering mechanism, the regulation processes of intracellular electrochemistry and the non-enzymatic power source of biochemistry, which are critical prerequisites for cellular functions and homeostasis. However, our understandings on the underlying molecular rules and their potential impacts on cellular functions are limited. In the next five years, we will uncover the molecular mechanisms by which intrinsically disordered proteins and biomolecular condensation can modulate local and spatial chemical environments (e.g., salt and water abundance) in the cytoplasm and how these environmental features can define the electrochemical equilibria of living cells (e.g., membrane potential, pH gradient). We will study how the phase transition process can encode interfacial electrical properties at the liquid-liquid interface of condensates and explore whether the various surface charging mechanisms studied in the physical chemistry of liquid-solid and liquid-air interfaces can be manifested on the condensate surface. Lastly, with these newly uncovered functioning principles of living cells, we will design new fundamental capabilities for synthetic biology to program cellular chemical and electrochemical features for diverse bioengineering applications (e.g., metabolic engineering). Considering the critical importance of cellular environments on biochemical functions and the ubiquitous nature of disordered proteins and condensates, the proposed research will introduce a novel framework for understanding the functioning principles of cell biology, expanding our knowledge on the machineries defining cellular physiology. Project Number: 1R35GM162028-01 | Fiscal Year: 2026 | NIH Institute/Center: National Institute of General Medical Sciences (NIGMS) | Principal Investigator: Yifan Dai | Institution: WASHINGTON UNIVERSITY, SAINT LOUIS, MO | Award Amount: $410,520 | Activity Code: R35 | Study Section: Maximizing Investigators' Research Award B Study Section[MRAB] View on NIH RePORTER: https://reporter.nih.gov/project-details/11265846