Research in the MacCallum lab explores problems in protein biophysics and structural biology using both experimental and computational approaches. Our focus is on problems where the right combination of experiment and computation can lead to progress.


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Integrative Structural Biology

How can we determine the structures of biomolecules and their complexes when the traditional approaches of X-ray crystallography and solution NMR have not worked? Integrative structural biology combines powerful computational models with often sparse, ambiguous, and unreliable data to infer the structures of biomolecules.

This line of research develops and applies new combinations of experiment and computation for structure determination. Specific projects include:

  • Automated structure determination from sparsely-labeled NMR experiments
  • NMR structure determination using the paramagnetic relaxation enhancement effect in both solution and solid-states
  • Using chemical cross-linking and solvent exposure mass spec experiments to infer the structure of proteins and complexes
  • Predicting protein structures from sequence data

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Biomolecular Recognition and Design

How does one molecule (e.g. a protein) recognize and bind tightly to another (e.g. protein or DNA)? These biomolecular recognition events are underly how information is relayed within the cell, but we lack quantitative physical models that can accurately predict affinity and specificity.

We approach this problem both by examining natural complexes and by designing new complexes that do not exist in nature.

By examining natural complexes, we aim to develop physical models that can explain how the sequence and structure affect binding affinity and specificity.

But the true test is to use what we've learned to design new non-natural interactions, which have a wide range of applications as new therapeutic molecules, biosensors and molecular diagnostics, and bio-nano materials.