Biomolecular Dynamics @ Uni Freiburg

Allosteric communication in proteins

Long-range effects in an allosteric protein

A local perturbation of a protein may lead to functional changes at some distal site. An example is the PDZ2 domain of human tyrosine phosphatase 1E, which shows an allosteric transition upon binding to a peptide ligand. Recently Buchli et al. presented a time- resolved study of this transition by covalently linking an azobenzene photoswitch across the binding groove and using a femtosecond laser pulse that triggers the cis−trans photoisomerization of azobenzene. To aid the interpretation of these experiments, in this work seven microsecond runs of all-atom molecular dynamics simulations each for the wild-type PDZ2 in the ligand-bound and -free state, as well as the photoswitchable protein (PDZ2S) in the cis and trans states of the photoswitch, in explicit water were conducted. First the theoretical model is validated by recalculating the available NMR data from the simulations. By comparing the results for PDZ2 and PDZ2S, it is analyzed to what extent the photoswitch indeed mimics the free-bound transition. A detailed description of the conformational rearrangement following the cis−trans photoisomerization of PDZ2S reveals a series of photoinduced structural changes that propagate from the anchor residues of the photoswitch via intermediate secondary structure segments to the C- terminus of PDZ2S. The changes of the conformational distribution of the C-terminal region is considered as the distal response of the isolated allosteric protein.
Long-Range Conformational Transition of a Photoswitchable Allosteric Protein: Molecular Dynamics Simulation Study S. Buchenberg, V. Knecht, and G. Stock J. Phys. Chem. B 118, 13468 (2014)

Binding of purine bases to guanine sensing riboswitch

Riboswitches are a novel class of genetic control elements that function through the direct interaction of small metabolite molecules with structured RNA elements. The ligand is bound with high specificity and affinity to its RNA target and induces conformational changes of the RNA's secondary and tertiary structure upon binding. To elucidate the molecular basis of the remarkable ligand selectivity and affinity of one of these riboswitches extensive all-atom molecular dynamics simulations in explicit solvent (≈1μs total simulation length) of the aptamer domain of the guanine sensing riboswitch are performed. The conformational dynamics is studied when the system is bound to its cognate ligand guanine as well as bound to the non-cognate ligand adenine and in its free form. The simulations indicate that residue U51 in the aptamer domain functions as a general docking platform for purine bases, whereas the interactions between C74 and the ligand are crucial for ligand selectivity. This findings suggest a two-step ligand recognition process, including a general purine binding step and a subsequent selection of the cognate ligand. To explore possible pathways of complex dissociation, various nonequilibrium simulations are performed which account for the first steps of ligand unbinding. The results suggest two possible pathways for the dissociation reaction and underline the importance of long-range tertiary contacts for locking the ligand in the complex.
Molecular dynamics simulation study of the binding of purine bases to the aptamer domain of guanine sensing riboswitch, A. Villa, J. Wähnert, and G. Stock, Nucl. Acids Res. 37, 4774 (2009)