Scientists map how proteins signal internally, opening doors for drug design
Researchers have unveiled the step-by-step molecular choreography behind protein signaling—the chemical messaging that controls how cells respond to their environment. By combining computer simulations with lab experiments, they traced these signals across billionths of a second, revealing that a single amino acid acts as a relay point. The work could accelerate development of drugs targeting diseases from cancer to neurodegeneration.
Originaltitel: Understanding structural dynamics of allostery across time and length scales
<p>Allostery constitutes the major mechanism of intraprotein and interprotein signaling. Detecting these signaling channels, their underlying structural rearrangements and especially transition dynamics is challenging as it requires a detailed analysis down to atomic scales and timescales that cover several orders of magnitude. We here present an integrative research approach to detect and follow allosteric information transfer across multiple time and length scales. We employ molecular dynamics simulations on a multi-μs scale combined with nanosecond fluorescence correlation spectroscopy and neutron scattering experiments, including neutron spin echo experiments, to verify the predicted dynamics and structural changes. Using the heat shock protein 90 (Hsp90) as test system, we reveal molecule-spanning and highly diffusive dynamics on the order of 100 ns that may serve as the dynamical basis for allosteric changes. Furthermore, we can follow protein dynamics upon hydrolysis of ATP to ADP from Angstroms and nanoseconds (bond ruptures and local rearrangements) to nanometers and microseconds (protein domain reorientations). Intriguingly, a single amino acid is crucial for transferring structural information from the nucleotide-binding site to the full protein dimer.</p>