Rate of Loop Formation in Peptides: A Simulation Study

Experimental techniques with high temporal and spatial resolution extend our knowledge of how biological macromolecules self-organise and function. Here, we provide an illustration of the convergence between simulation and experiment made possible by techniques such as triplet–triplet energy transfer and fluorescence quenching with long-lifetime and fast-quenching fluorescent probes. These techniques have recently been used to determine the average time needed for two residues in a peptide or protein segment to form a contact. The timescale of this process is accessible to computer simulation, providing a microscopic interpretation of the data and yielding new insight into the disordered state of proteins. Conversely, such experimental data also provide a test of the validity of alternative choices for the molecular models used in simulations, indicating their possible deficiencies. We carried out simulations of peptides of various composition and length using several models. End-to-end contact formation rates and their dependence on peptide length agree with experimental estimates for some sequences and some force fields but not for others. The deviations are due to artefactual structuring of some peptides, which is not observed when an atomistic model for the solvation water is used. Simulations show that the observed experimental rates are compatible with considerably different distributions of the end-to-end distance; for realistic models, these are never Gaussian but indicative of a rugged energy landscape.