Research

Research in the Herzik Lab focuses on understanding the molecular mechanisms that govern complex biological processes through the development and integration of innovative structural, biochemical, biophysical, and computational approaches. Our laboratory has a particular emphasis on advancing cryoEM technologies to investigate dynamic and heterogeneous macromolecular assemblies that are difficult to characterize using conventional methods. By combining fundamental mechanistic investigations with technological innovation, we aim to understand how protein structure and dynamics regulate biological function and identify new opportunities for therapeutic intervention.

Integrative Structural Biology and Molecular Mechanisms

Proteins are dynamic molecules that continuously change shape and interact with other cellular components to perform essential biological functions. These structural changes often govern how proteins recognize their partners, regulate biochemical reactions, and respond to changes in their cellular environment. Understanding these processes is essential for determining how complex molecular systems function and how their disruption contributes to human disease.

Our laboratory integrates cryoEM, X-ray crystallography, biochemical and biophysical approaches, and computational modeling to investigate the structural and mechanistic basis of protein function. A major focus of our research is mitochondrial protein homeostasis (proteostasis), particularly the molecular machinery responsible for protein import, folding, and quality control. We investigate how mitochondrial import receptors, molecular chaperones, and their interacting partners coordinate these essential processes and how their regulation may be altered in cancer and other diseases. More broadly, we seek to understand how protein conformational dynamics and transient molecular interactions can reveal previously unrecognized opportunities for therapeutic intervention.

CryoEM Technology and Method Development

CryoEM has revolutionized our ability to visualize biological macromolecules at near-atomic resolution. Despite these advances, many biologically important protein complexes remain challenging to investigate because of their structural flexibility, biochemical instability, or transient molecular interactions. Overcoming these limitations requires continued innovation in how biological specimens are prepared, preserved, and imaged.

Our laboratory develops novel technologies and experimental methodologies spanning the cryoEM workflow, with particular emphasis on specimen preparation, vitrification, and microscope optimization. These efforts include approaches for preserving fragile and oxygen-sensitive proteins, minimizing sample damage during freezing, and capturing transient structural intermediates through time-resolved experiments. By improving specimen quality, reproducibility, and experimental accessibility, we aim to expand the range of biological systems amenable to high-resolution cryoEM and enable structural investigations that would otherwise be inaccessible.

Computational Structural Biology and Artificial Intelligence

Modern structural biology increasingly relies on sophisticated computational approaches to interpret complex experimental data. In cryoEM, biological molecules are often captured in multiple conformational states, making it difficult to distinguish meaningful structural differences from experimental noise. Accurately identifying these states is essential for understanding how molecular dynamics contribute to biological function.

Our laboratory develops and applies innovative computational methods, including machine learning and artificial intelligence, to improve cryoEM data processing, three-dimensional reconstruction, and structural model validation. We are particularly interested in developing approaches that better identify and characterize structural heterogeneity, improve the accuracy and reproducibility of molecular reconstructions, and provide more reliable interpretations of dynamic biological systems. By integrating these computational advances with experimental structural biology, we aim to extract more meaningful mechanistic information from cryoEM data and establish broadly applicable tools for the structural biology community.

CryoEM Education, Training, and Mentorship

The rapid advancement of cryoEM and integrative structural biology has created an increasing need for accessible, hands-on training in both experimental and computational methodologies. Developing the next generation of structural biologists requires not only access to cutting-edge instrumentation but also a fundamental understanding of the principles, limitations, and practical considerations underlying high-resolution structure determination.

Our laboratory is committed to advancing cryoEM education through undergraduate and graduate instruction, hands-on workshops, and individualized scientific mentorship. We have contributed to national and international training initiatives that integrate foundational concepts with practical experience in specimen preparation, microscope operation, data collection, computational image processing, and structural model interpretation. Within the laboratory, we emphasize interdisciplinary training that combines structural biology with biochemistry, biophysics, and computational approaches, fostering both technical expertise and independent scientific thinking.