Biomedical subjects

Collin M Stultz

Publications and source records attributed to Collin M Stultz.

5 recordsLinked to original sources

PubMed2006

Conformational sampling with implicit solvent models: application to the PHF6 peptide in tau protein.

Implicit solvent models approximate the effects of solvent through a potential of mean force and therefore make solvated simulations computationally efficient. Yet despite their computational efficiency, the inherent approximations made by implicit solvent models can sometimes lead to inaccurate results. To test the accuracy of a number of popular implicit solvent models, we determined whether implicit solvent simulations can reproduce the set of potential energy minima obtained from explicit solvent simulations. For these studies, we focus on a six-residue amino-acid sequence, referred to as the paired helical filament 6 (PHF6), which may play an important role in the formation of intracellular aggregates in patients with Alzheimer's disease. Several implicit solvent models form the basis of this work--two based on the generalized Born formalism, and one based on a Gaussian solvent-exclusion model. All three implicit solvent models generate minima that are in good agreement with minima obtained from simulations with explicit solvent. Moreover, free-energy profiles generated with each implicit solvent model agree with free-energy profiles obtained with explicit solvent. For the Gaussian solvent-exclusion model, we demonstrate that a straightforward ranking of the relative stability of each minimum suggests that the most stable structure is extended, a result in excellent agreement with the free-energy profiles. Overall, our data demonstrate that for some peptides like PHF6, implicit solvent can accurately reproduce the set of local energy minimum arising from quenched dynamics simulations with explicit solvent. More importantly, all solvent models predict that PHF6 forms extended beta-structures in solution, a finding consistent with the notion that PHF6 initiates neurofibrillary tangle formation in patients with Alzheimer's disease.

Alzheimer Disease↗

PubMed2006

The folding mechanism of collagen-like model peptides explored through detailed molecular simulations.

Collagen has a unique folding mechanism that begins with the formation of a triple-helical structure near its C terminus followed by propagation of this structure to the N terminus. To elucidate factors that affect the folding of collagen, we explored the folding pathway of collagen-like model peptides using detailed molecular simulations with explicit solvent. Using biased molecular dynamics we examined the latter stages of folding of a peptide model of native collagen, (Pro-Hyp-Gly)10, and a peptide that models a Gly --> Ser mutation found in several forms of osteogenesis imperfecta, (Pro-Hyp-Gly)3-Pro-Hyp-Ser-(Pro-Hyp-Gly)6. Starting from an unfolded state that contains a C-terminal nucleated trimer, (Pro-Hyp-Gly)10 folds to a structure where two of the three chains associate through water-mediated hydrogen bonds and the third is relatively separated from this dimer. Calculated free-energy profiles for folding from this intermediate to the final triple-helical structure suggest that further folding occurs at a rate of approximately one Pro-Hyp-Gly triplet per msec. In contrast, after 6 nsec of biased dynamics, the region N-terminal to the Ser residue in (Pro-Hyp-Gly)3-Pro-Hyp-Ser-(Pro-Hyp-Gly)6 folds to a structure where the three chains form close contacts near the N terminus, away from the mutation site. Further folding to an ideal triple-helical structure at the site of the mutation is unfavorable as the free energy of a triple-helical conformation at this position is more than 20 kcal/mol higher than that of a structure with unassociated chains. These data provide insights into the folding pathway of native collagen and the events underlying the formation of misfolded structures.

Amino Acid Sequence↗

PubMed2003

A structural model that explains the effects of hyperglycemia on collagenolysis.

Prior investigations into the effects hyperglycemia on collagen degradation have yielded conflicting results. We present a new formalism for understanding the biochemistry of collagenolysis and the effects of hyperglycemia on collagen degradation. The analysis is based on an understanding of environments that affect the conformational stability of collagen. We suggest that collagen can exist in two distinct conformational states-a native state and a vulnerable state. Vulnerable collagen corresponds to a non-native conformation where partially unfolded regions near collagenase cleavage sites enable collagenases to efficiently degrade collagen. Theoretical calculations on collagen-like model peptides suggest that relatively short periods of hyperglycemia can alter the equilibrium distribution of states to favor vulnerable states of collagen. These data provide new insights into the mechanism of collagenolysis and resolve apparently discrepant experimental data on the effects of hyperglycemia on collagen degradation.

Animals↗

PubMed2002

Phosphorylation-induced conformational changes in a mitogen-activated protein kinase substrate. Implications for tyrosine hydroxylase activation.

Mitogen-activated protein (MAP) kinase-mediated phosphorylation of specific residues in tyrosine hydroxylase leads to an increase in enzyme activity. However, the mechanism whereby phosphorylation affects enzyme turnover is not well understood. We used a combination of fluorescence resonance energy transfer (FRET) measurements and molecular dynamics simulations to explore the conformational free energy landscape of a 10-residue MAP kinase substrate found near the N terminus of the enzyme. This region is believed to be part of an autoregulatory sequence that overlies the active site of the enzyme. FRET was used to measure the effect of phosphorylation on the ensemble of peptide conformations, and molecular dynamics simulations generated free energy profiles for both the unphosphorylated and phosphorylated peptides. We demonstrate how FRET transfer efficiencies can be calculated from molecular dynamics simulations. For both the unphosphorylated and phosphorylated peptides, the calculated FRET efficiencies are in excellent agreement with the experimentally determined values. Moreover, the FRET measurements and molecular simulations suggest that phosphorylation causes the peptide backbone to change direction and fold into a compact structure relative to the unphosphorylated state. These results are consistent with a model of enzyme activation where phosphorylation of the MAP kinase substrate causes the N-terminal region to adopt a compact structure away from the active site. The methods we employ provide a general framework for analyzing the accessible conformational states of peptides and small molecules. Therefore, they are expected to be applicable to a variety of different systems.

Animals↗

PubMed2002

Localized unfolding of collagen explains collagenase cleavage near imino-poor sites.

Collagenases cleave all three chains of type III collagen at specific sites characterized by a Gly-Leu or a Gly-Ile bond that is upstream from an imino acid-poor region. Molecular dynamics trajectories were used to calculate the free energy of unfolding for collagen-like model peptides. The free energy profiles suggest that such imino-poor regions can adopt a low-energy, partially unfolded state where one of the peptide chains forms a solvent-exposed loop. The results are consistent with a model for collagenase cleavage where partial unfolding of imino-poor regions enables collagenases to gain access to their cleavage sites.

Amino Acid Sequence↗