From helix–coil transitions to protein folding

Abstract

An evolution of procedures to simulate protein structure and folding pathways is described. From an initial focus on the helix-coil transition and on hydrogen-bonding and hydrophobic interactions, our original attempts to determine protein structure and folding pathways were based on an experimental approach. Experiments on the oxidative folding of reduced bovine pancreatic ribonuclease A (RNase A) led to a mechanism by which the molecule folded to the native structure by a minimum of four different pathways. The experiments with RNase A were followed by development of a molecular mechanics approach, first, making use of global optimization procedures and then with molecular dynamics (MD), evolving from an all-atom to a united-residue model. This hierarchical MD approach facilitated probing of the folding trajectory to longer time scales than with all-atom MD, and hence led to the determination of complete folding trajectories, thus far for a protein containing as many as 75 amino acid residues. With increasing refinement of the computational procedures, the computed results are coming closer to experimental observations, providing an understanding as to how physics directs the folding process. Keywords helix-coil transition; polyamino acids; collagen Elkan Blout played a very important role in the experimental studies of the helix-coil transition by developing methods to synthesize high-molecular-weight poly-α-amino acids, 2,10-16 to study their properties, including the helix-coil transition, 17-21 with optical rotation, 22-29 circular dichroism, 30,31 and infrared spectroscopy, 32-38 and by demonstrating the biological properties of some of these homopolymers, e.g., their antigenicity. 39 He also developed

Prediction of protein folding rates from primary sequence by fusing multiple sequential features

“…K of Eq.7.6 is involved with more parameters because the 6-th feature 6  contains three sub-features (cf. Eq.6).…”

“…Failure to fold into the intended 3D structure usually produces inactive proteins with different properties. Although many efforts have been made trying to understand the mechanism of protein folding (see, e.g., [3,4,5,6]), it still remains one of the most challenging problems in molecular biology. In addition to understanding how a protein chain is folded, it is also important to find the folding rates of proteins from their primary sequences.…”

Evaluation of electrospun PLLA-ECM scaffolds as biomaterials for bone regeneration

“…Moreover, trypsin proved to be the most specific enzyme and forms a limited number of fragments. In addition to the differences between the three enzymes comparing the cleavage sites, some reports suggest that hydrogen bonds between N--H and C=O groups from the polypeptide chain backbone play an important role in the interactions of side--chain groups between interresidues and limited proteolysis (Scheraga 2008). Regarding the limited proteolysis, the disruption of the hydrogen bond is an endothermic event that requires the entropic gain from the hydrolysis by the liberation of a peptide fragment.…”

“…The peptide group released is involved in the backbone from where hydrogen bonds must be broken. Furthermore, the proteolysis is limited because the enzyme takes part in an equilibrium, whereas the enzyme can catalyse the formation of peptide bonds between the fragments (Scheraga 2008). …”

“…Thus, P--ECM structure is more susceptible to the enzymatic proteolysis. Scheraga reported that the rupture of backbone hydrogen bonds from the residue favours, thermodynamically, peptide bond hydrolysis (Scheraga 2008). Therefore, less stable triple--helix are subjected to higher degradation via hydrolysis.…”