The folding thermodynamics and kinetics of crambin using an all-atom Monte Carlo simulation.
We present a novel Monte Carlo simulation of protein folding, in which all heavy atoms are represented as interacting hard spheres. This model includes all degrees of freedom relevant to folding, all side-chain and backbone torsions, and uses a Go potential. In this study, we focus on the 46 residue alpha/beta protein crambin and two of its structural components, the helix and helix hairpin. For a wide range of temperatures, we recorded multiple folding events of these three structures from random coils to native conformations that differ by less than 1 A C(alpha) dRMS from their crystal structure coordinates. The thermodynamics and kinetic mechanism of the helix-coil transition obtained from our simulation shows excellent agreement with currently available experimental and molecular dynamics data. Based on insights obtained from folding its smaller structural components, a possible folding mechanism for crambin is proposed. We observed that the folding occurs via a cooperative, first order-like process, and that many folding pathways to the native state exist. One particular sequence of events constitutes a "fast-folding" pathway where kinetic traps are avoided. At very low temperatures, a kinetic trap arising from the incorrect packing of side-chains was observed. These results demonstrate that folding to the native state can be observed in a reasonable amount of time on desktop computers even when an all-atom representation is used, provided the energetics sufficiently stabilize the native state.
Shimada
J
J
Department of Chemistry and Chemical Biology, Harvard University, 12 Oxford Street, Cambridge, MA, 02138, USA.
Kussell
E L
EL
Shakhnovich
E I
EI
D000495:Allosteric Site; D003198:Computer Simulation; D007700:Kinetics; D008958:Models, Molecular; D009010:Monte Carlo Method; D010940:Plant Proteins / Q000737:chemistry* / Q000378:metabolism*; D011487:Protein Conformation; D017510:Protein Folding; D015203:Reproducibility of Results; D013696:Temperature; D013816:Thermodynamics
D010940:Plant Proteins; C024934:crambin protein, Crambe abyssinica