About

Frank Heinrich is a research professor affiliated with the NCNR at NIST. His research focuses on biological physics and supramolecular structures, contributing to the understanding of complex biological systems through physical and structural analysis techniques. His work involves collaboration across institutions, notably Carnegie Mellon University and the NIST Center for Neutron Research, emphasizing the study of supramolecular assemblies and their properties.

Research topics

• Cancer research
• Chemistry
• Cell biology
• Biochemistry
• Biology

Selected publications

• Harnessing Membrane-Active Peptides for Selective Cancer Targeting: Phosphatidylserine Recognition by Tilapia Piscidin 4

  JACS Au · 2026-04-07

  articleOpen access

  Membrane-active peptides (MAPs) have garnered significant attention as potential alternatives to conventional cancer therapies, which are frequently limited by severe side effects. Among them, antimicrobial peptides (AMPs) that leverage differences between the plasma membranes of cancer cells and healthy cells are particularly attractive. While several AMPs have demonstrated anticancer potency, structure-function relationship studies are lacking to explain the molecular basis of their selectivity and to help design improved analogs. Here, we contribute to filling this gap by investigating Nile tilapia piscidin 4 (TP4), an AMP with demonstrated activity against several solid organ cancers. First, we discover through biological assays that the anticancer activity of the peptide, which underscores a promising therapeutic window, is associated with increased plasma membrane permeability in cancer cells compared to normal cells and positively (negatively) correlated with enzymes that enrich (deplete) anionic PS in the outer leaflet. Next, we utilize a suite of complementary techniques on model membranes to investigate the interactions of TP4 with membranes, uncovering behaviors not previously observed in related AMPs. Circular dichroism experiments reveal that TP4 preferentially binds to zwitterionic phosphatidylcholine (PC) membranes enriched in anionic PS, while cholesterol markedly impairs binding. X-ray diffraction demonstrates that TP4 disrupts PC-PS membranes by inducing lipid segregation. Covering a range of biologically relevant peptide concentrations with neutron diffraction and reflectometry measurements in fluid bilayers and MD simulations, we unveil how TP4 and associated water gradually insert into the hydrocarbon region and cause convoluted membrane deformations to breach the membrane barriers. These studies highlight the pivotal role of the TP4 polyarginine tail in driving selective membrane binding and disruption on membranes enriched with the anionic lipid PS. Together, our results elucidate the molecular determinants underpinning the selective anticancer effects of TP4, providing a strategic framework for the rational design of advanced membrane-active therapeutics.

  PublisherDOI

• Complex Structural Examination of Protein–Lipid Interactions with Neutron Scattering Techniques

  Methods in molecular biology · 2026-01-01

  book-chapter
  PublisherDOI

• BPS2026 – Probing the topology of membrane-bound KRAS and RAF using multiple biophysical approaches

  Biophysical Journal · 2026-02-01

  article
  PublisherDOI

• BPS2026 – Distribution, interaction preferences, and biophysical features of the tilapia piscidin 4 peptide within cancer cell membranes

  Biophysical Journal · 2026-02-01

  article
  PublisherDOI

• BPS2026 – Introducing the NIST ROADMAP project: AI-driven autonomous mapping of sequence-function relationships in membrane active peptides

  Biophysical Journal · 2026-02-01

  article
  PublisherDOI

• Abstract 4291 Linking antimicrobial peptide sequence to functional effects on lipid membrane structure

  Journal of Biological Chemistry · 2026-05-01

  articleOpen accessSenior author
  PublisherDOI

• BPS2026 – Characterization of membrane-active peptides on an automated solid supported lipid bilayer platform by neutron reflectometry

  Biophysical Journal · 2026-02-01

  article
  PublisherDOI

• Binding orientation of weakly associating membrane peripheral proteins via membrane paramagnetic relaxation enhancement NMR

  Communications Chemistry · 2026-04-24

  articleOpen access

  Cell-membrane signaling and trafficking rely on proteins that associate with lipid bilayers through dynamic, low-affinity interactions. Defining how these proteins dock onto membrane surfaces is therefore essential for understanding their function. While Neutron Reflectometry (NR) combined with molecular dynamics (MD) simulations is frequently used, complementary approaches that do not require access to large-scale neutron facilities are needed. Here, we establish membrane Paramagnetic Relaxation Enhancement (mPRE) Nuclear Magnetic Resonance (NMR), combined with nanodiscs as membrane mimics and optimized acquisition strategies, as an accessible solution for extracting membrane-protein distance constraints even for weakly bound systems. Using the PI(4,5)P₂-binding ASAP1 Pleckstrin Homology (PH) domain as a model, we show that both conventional mPRE and a new dynamic-exchange mPRE (EX-mPRE) method reproduce the membrane orientation obtained by NR. In addition, we show that increasing PI(4,5)P₂ levels to mimic nanoscale membrane clustering broadened the orientational distribution of ASAP1 PH. EX-mPRE, which transfers PREs from transient bound states to the observable free state, further enables studies of temperature-sensitive or rapidly exchanging membrane interactions. Together, these results provide the formalism and establish mPRE and EX-mPRE NMR as a powerful alternative for resolving the membrane orientation of peripheral proteins and for probing how lipid composition affects their behavior.

  PublisherOA PDFDOI

• BPS2025 - Modulating interactions between supported lipid bilayers and solid surfaces to study membrane active peptides by neutron reflectometry

  Biophysical Journal · 2025-02-01 · 1 citations

  article
  PublisherDOI

• An active allosteric mechanism in ASAP1-mediated Arf1 GTP hydrolysis redefines PH domain function

  Nature Communications · 2025-09-30 · 1 citations

  articleOpen access

  GTPase-activating proteins are important regulators of small GTPases; among these, ASAP1 stimulates GTP hydrolysis on Arf1 and is implicated in cancer progression. ASAP1 contains a Pleckstrin Homology (PH) domain essential for maximum Arf·GTP hydrolysis. The prevailing view of PH domains is that they regulate proteins through passive mechanisms like membrane recruitment. In sharp contrast, we show that the PH domain of ASAP1 actively contributes to Arf1 GTP hydrolysis. By combining NMR, molecular dynamics simulations, kinetic assays, and mutational analysis, we find that the PH domain binds Arf·GTP at the membrane, to establish an active state primed for GTP hydrolysis. We identify key residues on the PH domain and Arf that drive this allosteric mechanism, which mathematical modeling shows contributes as much to GTPase activation as membrane recruitment. The finding that PH domains directly modulate small GTPases has broad implications for the Ras and Rho oncoprotein families.

  PublisherOA PDFDOI

Frequent coauthors

• Mathias Lösche

  NIST Center for Neutron Research

  339 shared

• Hirsh Nanda

  Johnson & Johnson (United States)

  80 shared

• David J. Vanderah

  39 shared

• Duncan J. McGillivray

  Massey University

  38 shared

• Andrew Stephen

  Leidos Biomedical Research Inc. (United States)

  31 shared

• Stephanie Tristram‐Nagle

  Carnegie Mellon University

  30 shared

• C. F. Majkrzak

  NIST Center for Neutron Research

  30 shared

• Que N. Van

  Frederick National Laboratory for Cancer Research

  30 shared

Labs

• Supramolecular Structures LabPI

  The group of Professor Mathias Lösche focuses on common research objectives but with different aspects and techniques.

Education

• Ph.D., Nuclear Physics

  University of Leipzig (Germany)

  2005