Showing papers by "Adrian E. Roitberg published in 2008"

Exchange frequency in replica exchange molecular dynamics.

Abstract: The effect of the exchange-attempt frequency on sampling efficiency is studied in replica exchange molecular dynamics (REMD). We show that sampling efficiency increases with increasing exchange-attempt frequency. This conclusion is contrary to a commonly expressed view in REMD. Five peptides (1–21 residues long) are studied with a spectrum of exchange-attempt rates. Convergence rates are gauged by comparing ensemble properties between fixed length test REMD simulations and longer reference simulations. To show the fundamental correlation between exchange frequency and convergence time, a simple model is designed and studied, displaying the same basic behavior of much more complex systems.

A versatile AMBER-Gaussian QM/MM interface through PUPIL.

Abstract: The PUPIL package (Program for User Package Interfacing and Linking) originally was developed to interface different programs for multiscale calculations in materials sciences (Torras et al., J Comput Aided Mater Des 2006, 13, 201; Torras et al., Comput Phys Commun 2007, 177, 265). Here we present an extension of PUPIL to computational chemistry by interfacing two widely used computational chemistry programs: AMBER (molecular dynamics) and Gaussian (quantum chemistry). The benefit is to allow the application of the advanced MD techniques available in AMBER to a hybrid QM/MM system in which the forces and energy on the QM part can be computed by any of the methods available in Gaussian. To illustrate, we present two example applications: A MD calculation of alanine dipeptide in explicit water, and a use of the steered MD capabilities in AMBER to calculate the free energy of reaction for the dissociation of Angeli's salt. © 2008 Wiley Periodicals, Inc. J Comput Chem, 2008

Bond or cage effect: how nitrophorins transport and release nitric oxide.

Abstract: Most blood-sucking insects possess salivary proteins which, upon injection into the victim's tissue, help them improve their feeding. One group of these salivary proteins takes advantage of the vasodilator properties of NO to perform this task. These proteins are the so-called nitrophorins (NPs). NPs are heme proteins that store and transport NO, which, when released in the victim's tissue, produces vasodilation and inhibition of blood coagulation. It has been proposed that NO binds tightly to NP at a low pH of around 5.6 and that once NPs are injected in the victims tissue, at a pH of approximately 7.4, a conformational change occurs which lowers NO affinity, allowing it to be released. In this work we have studied the NO release mechanism of NP4 at a molecular level using state of the art computer simulation techniques. We have used molecular dynamics (MD) simulations to study NP4 conformational dynamics at both pH values 5.6 and 7.4 and computed the corresponding free energy profile for NO release usin...

Preliminary molecular dynamic simulations of the estrogen receptor alpha ligand binding domain from antagonist to apo.

Abstract: Estrogen receptors (ER) are known as nuclear receptors. They exist in the cytoplasm of human cells and serves as a DNA binding transcription factor that regulates gene expression. However the estrogen receptor also has additional functions independent of DNA binding. The human estrogen receptor comes in two forms, alpha and beta. This work focuses on the alpha form of the estrogen receptor. The ERα is found in breast cancer cells, ovarian stroma cells, endometrium, and the hypothalamus. It has been suggested that exposure to DDE, a metabolite of DDT, and other pesticides causes conformational changes in the estrogen receptor. Before examining these factors, this work examines the protein unfolding from the antagonist form found in the 3ERT PDB crystal structure. The 3ERT PDB crystal structure has the estrogen receptor bound to the cancer drug 4-hydroxytamoxifen. The 4-hydroxytamoxifen ligand was extracted before the simulation, resulting in new conformational freedom due to absence of van der Waals contacts between the ligand and the receptor. The conformational changes that result expose the binding clef of the co peptide beside Helix 12 of the receptor forming an apo conformation. Two key conformations in the loops at either end of the H12 are produced resulting in the antagonist to apo conformation transformation. The results were produced over a 42ns Molecular Dynamics simulation using the AMBER FF99SB force field.

Theoretical and Experimental Studies of Diruthenium Tetracarboxylates Structure, Spectroscopy, and Electrochemistry

Abstract: Quantum mechanical calculations at the density functional theory (DFT) level have been performed on diruthenium tetracarboxylates of different levels of molecular complexity: from unsolvated monomers to oligomers. The agreement between the calculated and experimental molecular structures and vibrational modes of the simple [Ru2(μ-O2CCH3)4]0/+and [Ru2(μ-O2CCH3)4(H2O)2]0/+ systems made us confident in our calculation methodology. Therefore, it has been applied to the analysis of two different kinds of properties of these compounds: the trends in the UV/vis spectroscopy and electrochemistry along the [Ru2(μ-O2CCH3)4X2]− (X = Cl−, Br−, I−) series, and the crystalline polymorphism related to the polymeric strand conformation in extended Ru2(μ-O2CR)4Cl compounds. For the [Ru2(μ-O2CCH3)4X2]− series, we report new spectroscopic and electrochemical results and interpret the trends on the basis of time dependent DFT-polarized continuum model calculations, local charge and spin analysis, and X donor properties. As f...

Using distances between α-carbons to predict protein structure

Abstract: Knowledge of a protein's structure is important in understanding its function. The usual experimental structure determination methods can be costly and time-consuming. We present an idea for a fast and inexpensive protein structure prediction method that combines modeling with less expensive experimental data. Our method involves three steps: (1) building a decoy set, (2) measuring inter-residue distances in a target protein, and (3) comparing the measured distances with those calculated in each decoy. We postulate that structures with a small number of similar inter-residue distances will also have similar three-dimensional structure. We further hypothesize that the minimum number of distances needed to determine structure is much less than the total number of inter-residue distances in the protein. To develop our protocol, we apply our method to target proteins whose structures have been solved experimentally but have not been included in the set. We simulate experimental data by calculating α-carbon distances from the experimentally determined structures of our target proteins. We have created a large, generalized decoy set using most of the structures in the Protein Data Bank. It can be used to study any protein composed of 100 residues or less. Using this decoy set, we searched for four proteins; our predicted structures ranged in RMSD from 3.6 to 7.7 A. We have also analyzed the RMSD distributions of the decoys using the search proteins as references and found the distributions to be similar for each protein. Of the nearly 5,000 CαCα distances in a 100 residue protein, knowledge of only twenty-five distances will usually result in predicting a reliable model. © 2008 Wiley Periodicals, Inc. Int J Quantum Chem, 2008

Simulating Temperature Jumps for Protein Folding

Abstract: We present a new computational methodology aimed to calculate the thermodynamics and kinetics of peptide folding. We focus in particular on temperature jump experiments of folding rates and show how a combination of replica exchange molecular dynamics (REMD) followed by multiplexed molecular dynamics starting from structures taken from the REMD runs can be used to extract properties in line with experiments. A model system, alanine20, is studied in this article as a proof of principle and used to describe the methodology.

Using the Rosetta algorithm and selected inter‐residue distances to predict protein structure

Abstract: The Rosetta algorithm has had much success in protein structure prediction as demonstrated in the recent Critical Assessment of Protein Structure Prediction (CASP) experiments. For many proteins, Rosetta generates several low root mean square deviation (RMSD) decoy structures but finding the best structure among the decoys can be difficult. Experimental data can be used to aid in the discrimination process. Our protein structure prediction method involves three steps: using the Rosetta algorithm to generate decoys, measuring inter-residue distances, and comparing the measured distances with those calculated in each decoy. Decoys with similar three-dimensional structure will also have several similar inter-residue distances. To develop our search protocol, we determined the optimal number of decoys to generate as well as the minimum number of distance constraints needed to distinguish between the low and high RMSD structures. To test our method, we simulate experimental data by measuring α-carbon distances from the experimentally determined structures of our target proteins. We have employed the Rosetta algorithm to generate decoy sets of different sizes for four target proteins. Our predicted structures ranged in Cα RMSD from 2.4 to 4.6 A compared with the experimental structures. Using only twenty-five distance constraints, reliable predictions were made. © 2008 Wiley Periodicals, Inc. Int J Quantum Chem, 2008

Quantifying Solvation Effects on Peptide Conformations: A QM/MM Replica Exchange Study

Abstract: We present replica exchange molecular dynamics calculations of the conformational space of alanine dipeptide, both in the gas phase and in water using both a classical force field potential and several commonly used semi-empirical QM/MM Hamiltonians implemented within the latest version of the AMBER software suite We present results comparing the performance of each method with experimental data for Ramachandran conformational distributions, NMR J coupling estimates and radial distribution functions for the peptide–solvent interactions