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To test the accuracy of existing AMBER force field models in predicting peptoid conformation and dynamics, we simulated a set of model peptoid molecules recently examined by Butterfoss et al. (JACS 2009, 131, 16798-16807) using QM methods as well as three peptoid sequences with experimentally determined structures. We found that AMBER force fields, when used w…

Peptoid molecules are biomimetic oligomers that can fold into unique three-dimensional structures. As part of an effort to advance computational design of folded oligomers, we present blind-structure predictions for three peptoid sequences using a combination of Replica Exchange Molecular Dynamics (REMD) simulation and Quantum Mechanical refinement. We correct…

The solution dynamics of antibodies are critical to antibody function. We explore the internal solution dynamics of antibody molecules through the combination of time-resolved fluorescence anisotropy experiments on IgG1 with more than two microseconds of all-atom molecular dynamics (MD) simulations in explicit water, an order of magnitude more than in previous…

Designing peptidomimetic compounds to have a preorganized structure in solution is highly nontrivial. To show how simulation-based approaches can help speed this process, we performed an extensive simulation study of designed cyclic peptide mimics of a β-hairpin from bacterial protein LapD involved in a protein-protein interaction (PPI) pertinent to bacte…

We present a Bayesian inference approach to estimating conformational state populations from a combination of molecular modeling and sparse experimental data. Unlike alternative approaches, our method is designed for use with small molecules and emphasizes high-resolution structural models, using inferential structure determination with reference potentials, a…

To test the ability of molecular simulations to accurately predict the solution-state conformational properties of peptidomimetics, we examined a test set of 18 cyclic RGD peptides selected from the literature, including the anticancer drug candidate cilengitide, whose favorable binding affinity to integrin has been ascribed to its pre-organization in solution…

The p53-MDM2 complex is both a major target for cancer drug development and a valuable model system for computational predictions of protein-ligand binding. To investigate the accuracy of molecular simulations of MDM2 and its complex with p53, we performed a number of long (200 ns to 1 µs) explicit-solvent simulations using a range of force fields. We sy…

Salt-bridge interactions play an important role in stabilizing many protein structures, and have been shown to be designable features for protein design. In this work, we study the effects of non-native salt bridges on the folding of a soluble alanine-based peptide (Fs peptide) using extensive all-atom molecular dynamics simulations performed on the Folding@ho…

Phenylalanine hydroxylase (PAH) regulates phenylalanine (Phe) levels in mammals to prevent neurotoxicity resulting from high Phe concentrations as observed in genetic disorders leading to hyperphenylalaninemia and phenylketonuria. PAH senses elevated Phe concentrations by transient allosteric Phe binding to a protein-protein interface between ACT domains of di…

One of the fundamental events in protein folding is α-helix formation, which involves sequential development of a series of helical hydrogen bonds between the backbone C═O group of residues i and the -NH group of residues i + 4. While we now know a great deal about α-helix folding dynamics, a key question that remains to be answered is where …