MOLECULAR-DYNAMICS SIMULATIONS OF EPIDERMAL GROWTH-FACTOR AND TRANSFORMING GROWTH-FACTOR-ALPHA STRUCTURES IN WATER

AMBER v 4.1 force field in 1.5 ns NPT molecular dynamics simulations o f murine epidermal growth factor (mEGF), human epidermal growth factor (hEGF), and human transforming growth factor-alpha (hTGF-alpha) struc tures with explicit TIP3P solvation were used to investigate differenc es in backbone stability, changes in secondary structure, interdomain flexibility, and weakly polar interactions. Backbone root mean square deviations of sections of each peptide show that the most stable regio ns in mEGF and hEGF are the A-, B-, and C-loops, whereas the most stab le regions in hTGF-alpha are the A- and B-loops, The secondary structu re in the B-loops of mEGF and hEGF differ significantly from the nucle ar magnetic resonance (NMR) structures of mEGF and hEGF. The position and type of turns in the B-loop of mEGF and hEGF increase the interstr and distance of the antiparallel beta-sheets thereby disrupting their structure, The interdomain flexibility of simulated hTGF-alpha structu re is greater than in either mEGF or hEGF. The phi, psi dihedrals of h TGF-alpha occupy two distinct populations of phase space corresponding to either a C-7(eq) or an alpha-helical conformation. This change in dihedral angle is stabilized by Phe(15) with Arg(42) and Phe(17) with Arg(42) N-pi weakly polar interactions that are present only in hTGF-a lpha but not in mEGF or hEGF. Proteins 33:396-407, 1998, (C) 1998 Wile y-Liss, Inc.