Comparison of multiple Amber force fields and development of improved protein backbone parameters

Horn̆ák, Viktor; Abel, Robert; Okur, Asim; Strockbine, Bentley; Roitberg, Adrián E.; Simmerling, Carlos

doi:10.1002/prot.21123

Cited by 6,369 publications

(6,392 citation statements)

References 72 publications

Supporting

Mentioning

6,167

Contrasting

Unclassified

Order By: Relevance

“…The current study was performed using the coordinates from the three X-ray structures of the CaM/IQ complex referred to as models A, B, and C (PDB code 2BE6) and models generated by molecular dynamics (MD) simulations at 300 K applying the amber99sb force field. 72 The simulations were carried out in GROMACS, 73 using the standard parameters delivered by the authors of the software. In total, two MD simulations of 120 ns were performed, starting from either model A or C, and the coordinates were recorded every 5 ps for a total of 48 000 MD models (24 000 from each simulation).…”

Section: ■ Materials and Methodsmentioning

confidence: 99%

Interdomain Dynamics Explored by Paramagnetic NMR

et al. 2013

View full text Add to dashboard Cite

An ensemble-based approach is presented to explore the conformational space sampled by a multidomain protein showing moderate interdomain dynamics in terms of translational and rotational motions. The strategy was applied on a complex of calmodulin (CaM) with the IQ-recognition motif from the voltage-gated calcium channel Ca v 1.2 (IQ), which adopts three different interdomain orientations in the crystal. The N60D mutant of calmodulin was used to collect pseudocontact shifts and paramagnetically induced residual dipolar couplings for six different lanthanide ions. Then, starting from the crystal structure, pools of conformations were generated by free MD. We found the three crystal conformations in solution, but four additional MD-derived conformations had to be included into the ensemble to fulfill all the paramagnetic data and cross-validate optimally against unused paramagnetic data. Alternative approaches led to similar ensembles. Our "ensemble" approach is a simple and efficient tool to probe and describe the interdomain dynamics and represents a general method that can be used to provide a proper ensemble description of multidomain proteins.

show abstract

Section: ■ Materials and Methodsmentioning

confidence: 99%

Interdomain Dynamics Explored by Paramagnetic NMR

et al. 2013

View full text Add to dashboard Cite

show abstract

“…The Amber11 software package 44 utilizing the Amber ff99SB potential functions 45 for proteins was used to perform the REMD simulations. The Onufriev− Bashford−Case implicit solvent model was chosen to represent the solution environment around the protein in order to avoid possible confined aqueous volume effects and specific heat errors on the simulated structures.…”

Section: ■ Methodsmentioning

confidence: 99%

Arginine and Disordered Amyloid-β Peptide Structures: Molecular Level Insights into the Toxicity in Alzheimer’s Disease

Coskuner

Wise-Scira

2013

ACS Chem. Neurosci.

View full text Add to dashboard Cite

Recent studies present that the single arginine (R) residue in the sequence of Aβ42 adopts abundant β-sheet structure and forms stable salt bridges with various residues. Furthermore, experiments proposed that R stimulates the Aβ assembly and arginine (R) to alanine (A) mutation (R5A) decreases both aggregate formation tendency and the degree of its toxicity. However, the exact roles of R and R5A mutation in the structures of Aβ42 are poorly understood. Extensive molecular dynamics simulations along with thermodynamic calculations present that R5A mutation impacts the structures and free energy landscapes of the aqueous Aβ42 peptide. The β-sheet structure almost disappears in the Ala21−Ala30 region but is more abundant in parts of the central hydrophobic core and C-terminal regions of Aβ42 upon R5A mutation. More abundant α-helix is adopted in parts of the N-terminal and mid-domain regions and less prominent α-helix formation occurs in the central hydrophobic core region of Aβ42 upon R5A mutation. Interestingly, intramolecular interactions between N-and C-terminal or mid-domain regions disappear upon R5A mutation. The structures of Aβ42 are thermodynamically less stable and retain reduced compactness upon R5A mutation. R5A mutant-type structure stability increases with more prominent central hydrophobic core and mid-domain or C-terminal region interactions. Based on our results reported in this work, small organic molecules and antibodies that avoid β-sheet formation in the Ala21−Ala30 region and hinder the intramolecular interactions occurring between the N-terminal and mid-domain or C-terminal regions of Aβ42 may help to reduce Aβ42 toxicity in Alzheimer's disease.

show abstract

“…37,38 The REMD simulations were performed with the AMBER 11 software package along with Amber ff99SB potential functions for the protein. 50,51 A total number of 56 replicas were utilized with temperatures exponentially distributed between 283 and 490 K. 52 The initial structures were equilibrated for 500 ns for each replica with a time step of 2 fs. Each replica was then simulated for a total of 40 ns with exchanges attempted every 5 ps while trajectories were saved every 500 steps.…”

Section: ■ Methodsmentioning

confidence: 99%

Structures and Free Energy Landscapes of the Wild-Type and A30P Mutant-Type α-Synuclein Proteins with Dynamics

Wise-Scira¹,

Aloglu²,

Dunn³

et al. 2013

ACS Chem. Neurosci.

View full text Add to dashboard Cite

The genetic missense A30P mutation of the wild-type α-synuclein protein results in the replacement of the 30th amino acid residue from alanine (Ala) to proline (Pro) and was initially found in the members of a German family who developed Parkinson's disease. Even though the structures of these proteins have been measured before, detailed understanding about the structures and their relationships with free energy landscapes is lacking, which is of interest to provide insights into the pathogenic mechanism of Parkinson's disease. We report the secondary and tertiary structures and conformational free energy landscapes of the wild-type and A30P mutant-type α-synuclein proteins in an aqueous solution environment via extensive parallel tempering molecular dynamics simulations along with thermodynamic calculations. In addition, we present the residual secondary structure component transition stabilities at the atomic level with dynamics in terms of free energy change calculations using a new strategy that we reported most recently. Our studies yield new interesting results; for instance, we find that the A30P mutation has local as well as long-range effects on the structural properties of the wild-type α-synuclein protein. The helical content at Ala18-Gly31 is less prominent in comparison to the wild-type α-synuclein protein. The β-sheet structure abundance decreases in the N-terminal region upon A30P mutation of the wild-type α-synuclein, whereas the NAC and C-terminal regions possess larger tendencies for β-sheet structure formation. Long-range intramolecular protein interactions are less abundant upon A30P mutation, especially between the NAC and C-terminal regions, which is linked to the less compact and less stable structures of the A30P mutant-type rather than the wild-type α-synuclein protein. Results including the usage of our new strategy for secondary structure transition stabilities show that the A30P mutant-type α-synuclein tendency toward aggregation is higher than the wild-type α-synuclein but we also find that the C-terminal and NAC regions of the A30P mutant-type α-synuclein are reactive toward fibrillzation and aggregation based on atomic level studies with dynamics in an aqueous solution environment. Therefore, we propose that small molecules or drugs blocking the specific residues, which we report herein, located in the NAC-and C-terminal regions of the A30P mutant-type α-synuclein protein might help to reduce the toxicity of the A30P mutant-type α-synuclein protein.

show abstract

Comparison of multiple Amber force fields and development of improved protein backbone parameters

Cited by 6,369 publications

References 72 publications

Interdomain Dynamics Explored by Paramagnetic NMR

Interdomain Dynamics Explored by Paramagnetic NMR

Arginine and Disordered Amyloid-β Peptide Structures: Molecular Level Insights into the Toxicity in Alzheimer’s Disease

Structures and Free Energy Landscapes of the Wild-Type and A30P Mutant-Type α-Synuclein Proteins with Dynamics

Contact Info

Product

Resources

About