Minimum free energy pathways and free energy profiles for conformational transitions based on atomistic molecular dynamics simulations

2007 ◽  
Vol 126 (16) ◽  
pp. 164106 ◽  
Author(s):  
Arjan van der Vaart ◽  
Martin Karplus
Keyword(s):  
Molecular Dynamics ◽  
Free Energy ◽  
Molecular Dynamics Simulations ◽  
Conformational Transitions ◽  
Minimum Free Energy ◽  
Energy Profiles ◽  
Dynamics Simulations ◽  
Free Energy Profiles ◽  
Energy Pathways

Displacement of carbonates in Ca2UO2(CO3)3 by amidoxime-based ligands from free-energy simulations

2018 ◽  
Vol 47 (5) ◽  
pp. 1604-1613 ◽  
Author(s):  
Bo Li ◽  
Chad Priest ◽  
De-en Jiang
Keyword(s):  
Molecular Dynamics ◽  
Free Energy ◽  
Molecular Dynamics Simulations ◽  
Umbrella Sampling ◽  
Nacl Solution ◽  
Classical Molecular Dynamics ◽  
Energy Profiles ◽  
Energy Simulations ◽  
Dynamics Simulations ◽  
Free Energy Profiles

Classical molecular dynamics simulations coupled with umbrella sampling reveal the atomistic processes and free-energy profiles of the displacement of carbonate groups in the Ca2UO2(CO3)3 complex by amidoxime-based ligands in a 0.5 M NaCl solution.

scholarly journals Ring Puckering Landscapes of Glycosaminoglycan-Related Monosaccharides from Molecular Dynamics Simulations

2019 ◽  
Author(s):  
Irfan Alibay ◽  
Richard Bryce
Keyword(s):  
Molecular Dynamics ◽  
Free Energy ◽  
Molecular Dynamics Simulations ◽  
Biological Function ◽  
Enhanced Sampling ◽  
Energy Profiles ◽  
Ring Puckering ◽  
Dynamics Simulations ◽  
Ring Pucker ◽  
Free Energy Profiles

<p>The conformational flexibility of the glycosaminoglycans (GAGs) are known to be key in their binding and biological function, for example in regulating coagulation and cell growth. In this work, we employ enhanced sampling molecular dynamics simulations to probe the ring conformations of GAG-related monosaccharides, including a range of acetylated and sulfated GAG residues. We first perform unbiased MD simulations of glucose anomers and the epimers glucoronate and iduronate. These calculations indicate that in some cases, an excess of 15 microseconds are required for adequate sampling of ring pucker due to the high energy barriers between states. However, by applying our recently developed msesMD simulation method (multidimensional swarm enhanced sampling molecular dynamics), we were able to quantitatively and rapidly reproduce these ring pucker landscapes. From msesMD simulations, the puckering free energy profiles were then compared for eleven monosaccharides found in GAGs; this includes to our knowledge the first simulation study of sulfation effects on GalNAc ring puckering. For the force field employed, we find that in general the calculated pucker free energy profiles for sulfated sugars were similar to the corresponding unsulfated profiles. This accords with recent experimental studies suggesting that variation in ring pucker of sulfated GAG residues is primarily dictated by interactions with surrounding residues rather than by intrinsic conformational preference. As an exception to this, however, we predict that 4-O-sulfation of GalNAc leads to reduced ring rigidity, with a significant lowering in energy of the <sup>1</sup>C<sub>4</sub> ring conformation; this observation may have implications for understanding the structural basis of the biological function of GalNAc-containing glycosaminoglycans such as dermatan sulfate.</p>

scholarly journals Ring Puckering Landscapes of Glycosaminoglycan-Related Monosaccharides from Molecular Dynamics Simulations

2019 ◽  
Author(s):  
Irfan Alibay ◽  
Richard Bryce
Keyword(s):  
Molecular Dynamics ◽  
Free Energy ◽  
Molecular Dynamics Simulations ◽  
Biological Function ◽  
Enhanced Sampling ◽  
Energy Profiles ◽  
Ring Puckering ◽  
Dynamics Simulations ◽  
Ring Pucker ◽  
Free Energy Profiles

<p>The conformational flexibility of the glycosaminoglycans (GAGs) are known to be key in their binding and biological function, for example in regulating coagulation and cell growth. In this work, we employ enhanced sampling molecular dynamics simulations to probe the ring conformations of GAG-related monosaccharides, including a range of acetylated and sulfated GAG residues. We first perform unbiased MD simulations of glucose anomers and the epimers glucoronate and iduronate. These calculations indicate that in some cases, an excess of 15 microseconds are required for adequate sampling of ring pucker due to the high energy barriers between states. However, by applying our recently developed msesMD simulation method (multidimensional swarm enhanced sampling molecular dynamics), we were able to quantitatively and rapidly reproduce these ring pucker landscapes. From msesMD simulations, the puckering free energy profiles were then compared for eleven monosaccharides found in GAGs; this includes to our knowledge the first simulation study of sulfation effects on GalNAc ring puckering. For the force field employed, we find that in general the calculated pucker free energy profiles for sulfated sugars were similar to the corresponding unsulfated profiles. This accords with recent experimental studies suggesting that variation in ring pucker of sulfated GAG residues is primarily dictated by interactions with surrounding residues rather than by intrinsic conformational preference. As an exception to this, however, we predict that 4-O-sulfation of GalNAc leads to reduced ring rigidity, with a significant lowering in energy of the <sup>1</sup>C<sub>4</sub> ring conformation; this observation may have implications for understanding the structural basis of the biological function of GalNAc-containing glycosaminoglycans such as dermatan sulfate.</p>

scholarly journals Exploring Conformational Transitions and Free Energy Profiles of Proton Coupled Oligopeptide Transporters

2019 ◽  
Author(s):  
Mariana R. B. Batista ◽  
Anthony Watts ◽  
Antonio J. Costa-Filho
Keyword(s):  
Free Energy ◽  
Conformational Changes ◽  
Conformational Transitions ◽  
Peptide Transport ◽  
Conformational Variability ◽  
Energy Profiles ◽  
Comprehensive Picture ◽  
Adaptive Biasing ◽  
Dynamics Simulations ◽  
Free Energy Profiles

AbstractProteins involved in peptide uptake and transport belong to the proton-coupled oligopeptide transporter (POT) family. Crystal structures of POT family members reveal a common fold consisting of two domains of six transmembrane α helices that come together to form a “V” shaped transporter with a central substrate binding site. Proton coupled oligopeptide transporters operate through an alternate access mechanism, where the membrane transporter undergoes global conformational changes, alternating between inward-facing (IF), outward-facing (OF) and occluded (OC) states. Conformational transitions are promoted by proton and ligand binding, however, due to the absence of crystallographic models of the outward-open state, the role of H+ and ligands are still not fully understood. To provide a comprehensive picture of the POT conformational equilibrium, conventional and enhanced sampling molecular dynamics simulations of PepTst in the presence or absence of ligand and protonation were performed. Free energy profiles of the conformational variability of PepTst were obtained from microseconds of adaptive biasing force (ABF) simulations. Our results reveal that both, proton and ligand, significantly change the conformational free energy landscape. In the absence of ligand and protonation, only transitions involving IF and OC states are allowed. After protonation of the residue Glu300, the wider free energy well for Glu300 protonated PepTst indicates a greater conformational variability relative to the apo system, and OF conformations becames accessible. For the Glu300 Holo-PepTst, the presence of a second free energy minimum suggests that OF conformations are not only accessible, but also, stable. The differences in the free energy profiles demonstrate that transitions toward outward facing conformation occur only after protonation and, probably, this should be the first step in the mechanism of peptide transport. Our extensive ABF simulations provide a fully atomic description of all states of the transport process, offering a model for the alternating access mechanism and how protonation and ligand control the conformational changes.Graphical TOC Entry

MM/PBSA analysis of molecular dynamics simulations of bovine β-lactoglobulin: Free energy gradients in conformational transitions?

2005 ◽  
Vol 59 (1) ◽  
pp. 91-103 ◽  
Author(s):  
Federico Fogolari ◽  
Elisabetta Moroni ◽  
Marcin Wojciechowski ◽  
Maciej Baginski ◽  
Laura Ragona ◽  
...  
Keyword(s):  
Molecular Dynamics ◽  
Free Energy ◽  
Molecular Dynamics Simulations ◽  
Conformational Transitions ◽  
Dynamics Simulations ◽  
Β Lactoglobulin

scholarly journals The trajectory of intrahelical lesion recognition and extrusion by the human 8-oxoguanine DNA glycosylase

2020 ◽  
Vol 11 (1) ◽  
Author(s):  
Uddhav K. Shigdel ◽  
Victor Ovchinnikov ◽  
Seung-Joo Lee ◽  
Jenny A. Shih ◽  
Martin Karplus ◽  
...  
Keyword(s):  
Molecular Dynamics ◽  
Free Energy ◽  
Dna Glycosylase ◽  
Dna Complexes ◽  
Repair Enzymes ◽  
Energy Profiles ◽  
Lesion Recognition ◽  
Dynamics Simulations ◽  
Free Energy Profiles ◽  
Dna Helix

Abstract Efficient search for DNA damage embedded in vast expanses of the DNA genome presents one of the greatest challenges to DNA repair enzymes. We report here crystal structures of human 8-oxoguanine (oxoG) DNA glycosylase, hOGG1, that interact with the DNA containing the damaged base oxoG and the normal base G while they are nested in the DNA helical stack. The structures reveal that hOGG1 engages the DNA using different protein-DNA contacts from those observed in the previously determined lesion recognition complex and other hOGG1-DNA complexes. By applying molecular dynamics simulations, we have determined the pathways taken by the lesion and normal bases when extruded from the DNA helix and their associated free energy profiles. These results reveal how the human oxoG DNA glycosylase hOGG1 locates the lesions inside the DNA helix and facilitates their extrusion for repair.

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