This page will give you a general overview of the major research focus of the Miller group as well as some insight into the different research projects that may be of interest. The group is engaged in a very broad range of research topics that are interrelated by the overarching goal to resolve the structure-function relationship of biological systems. The singular goal has required developing the necessary technology to go after this problem, from development of new laser technology to access different wavelength and temporal regimes, to new spectroscopies sensitive to different degrees of freedom, to ultrabright electron source technology. Students receive unique training in all these topics and can focus on areas related to nanotechnology, materials chemistry, and various aspects of time dependent ab initio methods and state of the art analytical methods for image reconstruction, depending on student interests.
The group’s research is driven by one of the central tenets of biology, i.e., biological systems have evolved to optimize their functions. At the molecular level, this degree of optimization reduces to factors that control barrier heights and transition state crossing processes. To a certain degree all of chemistry can be similarly reduced; one can expect that biology will be the ultimate teacher in mastering control over molecular processes. The trick is that biology has evolved away from homogeneous chemistry to elaborate heterogeneous chemical processes in which the local environment is exquisitely controlled. In this sense, biological molecules can be considered as nanobeakers in which highly structured environments (aka the protein matrix) are employed to highly direct chemical processes into motion or biological functions. Fundamentally biological processes are powered by chemical reactions, bonds being made or broken at active site, charge separation processes for energy storage or synthesis etc. Biology is effectively chemistry in motion. The intriguing issue is that biological processes occur orders of magnitude faster than a strictly random search of all possible degrees of freedom in directing the chemical processes into functions. In fact, the time scale is a condition for defining a living system (of 3); living systems must be catalytic. The structure-function relationship contains many of the same fundamental issues as Levinthal’s paradox. How do such large systems as proteins ever find their global minimum of their active state? It would take eons for a strongly associated system such as proteins to randomly search all the different nuclear configurations. It is clear that proteins do not randomly search their entire phase space but rather execute a highly constrained search in which there are inherent length scales in which that atoms move collectively. This highly correlated motion leads effectively to “coarse grain sampling” of the nuclear configurations. Of the 20,000+ protein structures that have been solved one sees a high reduction to a few distinct topological domains. These secondary helices, loops, beta sheets and quaternary contact points act to impose correlations on the different degrees of freedom. We introduced a concept referred to as “Collective Mode Coupling” to describe the mode selective displacements in biological systems (see Miller Acc. Chem. Res. 1994, Can. J. Chem. Polanyi Lecture 2001). It is our contention that this rather simple reduction to a few dominant low frequency modes in biological systems is the core of the structure-function relationship.
The different aspects of the research program are directed to further test and resolve this fundamental issue. As is often the case, on the way, we have encountered a number of equally puzzling and fundamental issues with respect to the degree of correlations in the medium of life – liquid H2O, coherent aspects of nuclear motions in biological systems, and issues of decoherence, structural changes in matter (at the atomic level of inspection) under strong driving conditions, and fundamental limits to scaling laser power re: laser source development to probe these issues.
To help guide you through the group’s research activities, the research can be broken different subgroups that may appear quite different in scope but as stated above are interrelated through the primary objective of the research program. These different research areas include:
- Femtosecond Electron Diffraction: “Making the Molecular Movie”
- Coherent Control and Multidimensional Coherent Spectroscopy of Complex Systems
- Nanofabrication and Novel Materials
- Theory and Big Data
- Solid State Laser Development
In addition, the group is heavily involved in knowledge translation, i.e., taking concepts out of the lab and into the “real” world. Currently there is a major effort in exploring applications in laser surgery and biodiagnostics where the lessons learned from the very first atomically resolved movies of laser driven phase transitions may very well lead to achieving the fundamental (single cell) limits to minimally invasive surgery and biodiagnostics (single protein) detection. Finally, science outreach is taken to be an important part of the group’s obligation to help foster science and to give back to the general public for their support. RJDM was the founder of Science Rendezvous, which is now one of the largest celebrations of science of its kind. These different research areas include:
Brief Synopsis of Research Activities.
The Femtosecond Electron Diffraction Laboratory has developed a novel ultrabright source of electron pulses that is now capable of watching atomic motions in real time in which full structural details can be retrieved at the single shot limit. This research area is dedicated to obtaining atomic level movies of structural changes with the long term goal of directly observing the structure-function correlation. The “film” for these movies must be on the order of 100 nm thick and there must be 100’s if not 10s of thousands of frames or samples on this scale to collect enough time points. This requirement places huge demands on samples and has led to major effort in nanotechnology to create the systems capable of probing different aspects of chemistry and biology. The amount of information that must be processed is enormous. The most basic diffraction experiment or reciprocal space imaging requires handling near Tbyte data streams. There are enormous challenges in both handing and connecting the results to atomic details. The group is now heavily involved in various analytical methods and time dependent ab initio methods to connect data to structures and structure to theory in a closed loop process. The Coherent Control program is aimed at probing vibrational coherences as a new means to inspect imposed correlations on nuclear motions along reaction coordinates in biological systems. There has also been a long term interest in liquid water. The basic premise is that we need to understand water at a first principles level if we ever hope to fully understand the protein-water interaction that breathes life into otherwise inanimate objects. This experimental program is aimed at directly probing anharmonic terms in the intermolecular potential of liquid water to experimentally define the key parameters needed to contrast the many body potential for liquid H2O in relation to other liquids. Several new spectroscopies have been developed to this end. Finally, the solid state laser program is the engine that drives the whole research program.
The Miller group is in many ways unique in that not only do we develop new spectroscopies but also new laser and electron source technology to open up new vistas for exploration. This technical expertise has led to a number of innovations that have been commercialized. (You have a 70% chance of flying in a plane with the wiring marked by our laser system. At one point, most of the high density circuit boards (e.g. autostabilization systems on video cameras) were drilled by a laser based on a prototype developed in our lab. At last count, former Miller group members have started up more than ten companies. More details on this part of the group activities can be found under Innovation Corner. The group is also deeply committed to science outreach to help the general public understand the importance of science. This activity has led to the founding of one of the largest experiments in engaging the public to answer the question “so what’s it good for?” as a way of giving back to the community for their support of this research (see Science Outreach).