Determination of three‐dimensional structures of proteins from interproton distance data by dynamical simulated annealing from a random array of atoms Circumventing problems associated with folding

TLDR

The authors present a real‑space simulated‑annealing method that determines protein structures from interproton distance restraints obtained by NMR. Starting from a random atom array, the method applies low force constants for covalent, distance, and van der Waals terms at high temperature, allowing atoms to move independently and overcome energy barriers before converging to the global minimum. The approach successfully locates the global minimum and is demonstrated on crambin and potato carboxypeptidase inhibitor.

Abstract

A new real space method, based on the principles of simulated annealing, is presented for determining protein structures on the basis of interproton distance restraints derived from NMR data. The method circumvents the folding problem associated with all real space methods described to date, by starting from a completely random array of atoms and introducing the force constants for the covalent, interproton distance and repulsive van der Waals terms in the target function appropriately. The system is simulated at high temperature by solving Newton's equations of motion. As the values of all force constants are very low during the early stages of the simulation, energy barriers between different folds of the protein can be overcome, and the global minimum of the target function is reliably located. Further, because the atoms are initially only weakly coupled, they can move essentially independently to satisfy the restraints. The method is illustrated using two examples of small proteins, namely crambin (46 residues) and potato carboxypeptidase inhibitor (39 residues).