The challenge of understanding biological systems from first physical principles is what motivates my research. Biological systems are characterized by remarkable structural complexity at all levels of organization. My research focuses on two of these levels: the molecular level and the systems level, attempting to bring them together in the analysis of biological phenomena. My laboratory develops multidisciplinary approaches involving computer simulations, evolutionary analysis and biophysical modeling to study how interactions between individual molecules give birth to complex biological systems.

Although molecular and systems levels of research biological activity operate on different size and time scales, there are numerous benefits in connecting these areas. By bringing them together, I would like to answer the following questions.

Complex biophysical processes such as protein folding, protein-DNA interactions and protein-protein interactions underlie the functioning of all biological systems, but the physics of molecular recognition is poorly understood. My goal is to understand the physical mechanisms behind specific molecular recognition and to develop computational tools to harness the exploding body of genomic information. For example, I want to determine the biophysical principles that allow proteins to find their specific DNA binding sites within seconds of a cellular signal, and to work out the physics and dynamics of the binding interaction. My laboratory develops models that simulate protein-DNA binding so that we can further probe this process. We also are studying the molecular evolution of proteins, using genomic and proteomic data to understand how proteins recognize each other and how the mechanisms for binding specificity evolved.

Molecular biology traditionally studies biological systems by reducing them to components and pathways that are simple enough to characterize in vitro. However, focusing on individual molecules and pathways does not lead one to a broad picture of the functioning of whole cells, tissues or organs. My goal is to develop a system-level understanding of biological circuits. This work combines bioinformatics techniques with computer simulation to model biological networks and study their dynamics and evolution. One such project in my laboratory involves the use of genomic and systems biology to characterize networks of protein-protein interactions in yeast. We are trying to deduce dynamics and function from information about system architecture. A second project focuses on the challenge of building a robust system from stochastic elements. All biological systems are comprised of molecules that participate in biochemical reactions, but these interactions are stochastic in nature. Systems built from probabilistic components should be unreliable but, in fact, biochemical pathways in living cells do work reliably. The goal of this project is to determine how it is possible to build a reliable system from intrinsically unreliable components.