Will molecular dynamics simulations of proteins ever reach equilibrium?

Genheden, Samuel; Ryde, Ulf

doi:10.1039/c2cp23961b

Cited by 85 publications

(124 citation statements)

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“…The difference in the RMSD values observed in the different system may be attributed to the different starting conformations of Aβ. Moreover, it has been shown that it is difficult to reach convergence even in 500 ns simulation in case of proteins [44]. Considering this issue, we have performed multiple simulations and used statistical analysis to probe the structural changes and dynamics of the peptide in different systems.…”

Section: Discussionmentioning

confidence: 99%

Effect of graphene oxide on the conformational transitions of amyloid beta peptide: A molecular dynamics simulation study

Baweja

Balamurugan

Subramanian

et al. 2015

Journal of Molecular Graphics and Modelling

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Section: Discussionmentioning

confidence: 99%

Effect of graphene oxide on the conformational transitions of amyloid beta peptide: A molecular dynamics simulation study

Baweja

Balamurugan

Subramanian

et al. 2015

Journal of Molecular Graphics and Modelling

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“…8,9,10,11,12 The latter two estimates seem to be very hard to converge to any useful precision, whereas NMA estimates of entropies converge much better. 10,11,12 In practice, the NMA calculations are performed by first stripping off all water molecules. Typically, the protein is also truncated by removing all residues more than ~8 Å from the ligand, 2 because the frequency calculations are very demanding in terms of computer time and memory.…”

Section: δG Bind = G(pl) -G(p) -G(l)mentioning

confidence: 97%

“…counting the number of rotable bonds in the ligand, dihedral-distribution histogramming, or quasi-harmonic analysis. 8,9,10,11,12 The latter two estimates seem to be very hard to converge to any useful precision, whereas NMA estimates of entropies converge much better. 10,11,12 In practice, the NMA calculations are performed by first stripping off all water molecules.…”

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confidence: 97%

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The Normal-Mode Entropy in the MM/GBSA Method: Effect of System Truncation, Buffer Region, and Dielectric Constant

Genheden

Kühn

Mikulskis

et al. 2012

J. Chem. Inf. Model.

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177

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We have performed a systematic study of the entropy term in the MM/GBSA (molecular mechanics combined with generalised Born and surface-area solvation) approach to calculate ligand-binding affinities. The entropies are calculated by a normal-mode analysis of harmonic frequencies from minimised snapshots of molecular dynamics simulations. For computational reasons, these calculations have normally been performed on truncated systems. We have studied the binding of eight inhibitors of blood clotting factor Xa, nine ligands of ferritin, and two ligands of HIV-1 protease and show that removing protein residues with distances larger than 8-16 Å to the ligand and including a 4 Å shell of fixed protein residues and water molecules, change the absolute entropies by 1-5 kJ/mol on average. However, the change is systematic, so relative entropies for different ligands change by only 0.7-1.6 kJ/mol on average. Consequently, entropies from truncated systems give relative binding affinities that are identical to those obtained for the whole protein within statistical uncertainty (1-2 kJ/mol). We have also tested to use a distance-dependent dielectric constant in the minimisation and frequency calculation (ε = 4r), but it typically gives slightly different entropies and poorer binding affinities. Therefore, we recommend entropies calculated with the smallest truncation radius (8 Å) and ε =1. Such an approach also gives an improved precision for the calculated binding free energies.Keywords: MM/GBSA, entropy, ligand-binding affinities, dielectric constant, factor Xa, ferritin, HIV-1 protease.Introduction MM/GBSA is an approximate method to estimate the absolute binding free energy, ΔG bind , of a ligand L, to a biomacromolecule, e.g. a protein, P, forming a complex PL. It estimates ΔG bind as the difference in free energy between PL, P, and L, viz. ΔG bind = G(PL) -G(P) -G(L). Each of these three free energies are estimated from the following sum 1,2 G = E int + E vdW + E ele + G solv + G np − TS MM ( 1) where the brackets indicate an average over snapshots from a molecular dynamics (MD) simulation. The first three terms on the right-hand side are the molecular mechanics (MM) internal (i.e. bonds, angles, and dihedral), van der Waals, and electrostatic energies, G solv and G np are the polar and nonpolar solvation free energies, and the last term is the absolute temperature multiplied by an entropy estimate. The latter estimate is usually taken as a combination of translational, rotational, and vibrational terms. All the terms are calculated on a system where water molecules from the simulation have been stripped off. Moreover, typically only the complex (PL) is simulated and the free energies of P and L are obtained from the same simulation by simply deleting the coordinates of the other species. 3,4 Thereby, the E int term cancels exactly and the precision is improved by a factor of ~5. 5,6 The most common method to estimate the vibrational entropy in the MM/GBSA method is to use frequencies from a normal-mode analysis (NMA...

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“…However, this did not occur invariably for every protein-ligand complex. This is natural for all MD simulations of proteins, as it has been shown that the equilibration of proteins in MD simulations is practically unfeasible (Genheden & Ryde 2012). Consequently, it is proposed that in place of one long simulation, several short runs should be considered for MM-GBSA based energy calculations (Genheden & Ryde 2010.…”

Section: Filamin a Interaction With Peptide-ligands 621 Mm-gbsa Is mentioning

confidence: 99%

Molecular mechanism of T-cell protein tyrosine phosphatase (TCPTP) activation by mitoxantrone

Ylilauri

Mattila

Nurminen

et al. 2013

Biochimica et Biophysica Acta (BBA) - Proteins and Proteomics

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Esitetään Jyväskylän yliopiston matemaattis-luonnontieteellisen tiedekunnan suostumuksella julkisesti tarkastettavaksi yliopiston Ylistönrinteellä, salissa YAA303 tammikuun 24. päivänä 2014 kello 12.Academic dissertation to be publicly discussed, by permission of the Faculty of Mathematics and Science of the University of Jyväskylä, in Ylistönrinne, hall YAA303, on January 24, 2014 at 12 o'clock noon. Ligand-binding in a specific manner is vital to all cellular actions and can have a major effect on the activity and conformation of proteins. In addition to experimental techniques, computational methods, such as molecular dynamics (MD) simulations, have become an integral part in studies related to proteinligand interactions. The computational approach introduces a dynamic view of molecular interactions, and enables detailed structure-function studies. In addition, it may facilitate the estimation of binding affinities and help in identifying ligand-binding sites in proteins. In this thesis three pharmacologically important protein targets were studied with both computational and experimental methods: 1) ionotropic glutamate receptors (iGluRs), 2) filamin A (FLNa), and 3) T-cell protein tyrosine phosphatase (TCPTP). iGluRs mediate synaptic transmission in the nervous system and are linked to many neurological disorders. Partial agonism of the ligand binding domains (LBD) for these receptors was studied with MD simulations and the molecular mechanics generalised Born surface area (MM-GBSA) method. A previously unobserved intermediate closure stage for the GluN1 receptor subtype was identified, and new information about the closure mechanism was obtained. FLNa is an actin cross-linking protein linked to many cellular functions via its numerous binding partners. MM-GBSA calculations of binding free energy were shown to correlate well with the experimental data. Thus, ligands could be ranked based on their binding affinity, suggesting that also the rational design of FLNa-binding peptide mimetics would be conceivable. TCPTP is a ubiquitously expressed non-transmembrane phosphatase that negatively regulates many cancer-related kinases. TCPTP is normally autoinhibited, but several agonist molecules are known to activate it. Here, a putative binding site for TCPTP activators was identified and important structural determinants for novel activators were recognised. As TCPTP is not down-regulated in cancer cells, it is a promising target for tumor suppression. UNIVERSITY

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Will molecular dynamics simulations of proteins ever reach equilibrium?

Cited by 85 publications

References 96 publications

Effect of graphene oxide on the conformational transitions of amyloid beta peptide: A molecular dynamics simulation study

Effect of graphene oxide on the conformational transitions of amyloid beta peptide: A molecular dynamics simulation study

The Normal-Mode Entropy in the MM/GBSA Method: Effect of System Truncation, Buffer Region, and Dielectric Constant

Molecular mechanism of T-cell protein tyrosine phosphatase (TCPTP) activation by mitoxantrone

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