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A new type of allosteric inhibition by small molecules is proposed that should be applicable to all proteins involved intrinsically in protein–protein interactions. It is based on targeting their rare interaction states that can be detected by high‐pressure NMR spectroscopy (see picture). An example is the Ras‐protein where the protein–protein interaction of Ras with effectors can be modulated by small compounds that bind to the conformational states 1(T) or 1(0).

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High pressure NMR spectroscopy has developed into an important tool for studying conformational equilibria of proteins in solution. We have studied the amide proton and nitrogen chemical shifts of the 20 canonical amino acids X in the random-coil model peptide Ac-Gly-Gly-X-Ala-NH2, in a pressure range from 0.1 to 200 MPa, at a proton resonance frequency of 800 MHz. The obtained data allowed the determination of first and second order pressure coefficients with high accuracy at 283 K and pH 6.7. The mean first and second order pressure coefficients and for nitrogen are 2.91 ppm/GPa and −2.32 ppm/GPa2, respectively. The corresponding values and for the amide protons are 0.52 ppm/GPa and −0.41 ppm/GPa2. Residual dependent 1J1H15N-coupling constants are shown.