When MELD Meets GaMD: Accelerating Biomolecular Landscape Exploration

Caparotta, Marcelo; Perez, Alberto

doi:10.1021/acs.jctc.3c01019

Cited by 2 publications

(2 citation statements)

References 60 publications

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“…Additionally, to validate the structure of sMyomerger (26–84) in Figure c, we used Modeling Employing Limited Data (MELD), a dedicated tool for inferring the structure of biomolecules, which combines REMD and GaMD. , The method introduces Gaussian biases to modulate the overlap in energy distributions along replicas and increases the number of round trips in the replica space, as well as the total number of clusters identified in the ensemble. For technical details on the use of MELD, please see Caparotta and Perez …”

Section: Methodsmentioning

confidence: 99%

Myomerger Induces Membrane Hemifusion and Regulates Fusion Pore Expansion

Di Bartolo,

Caparotta,

Polo

et al. 2024

Biochemistry

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Membrane fusion is a crucial mechanism in a wide variety of important events in cell biology from viral infection to exocytosis. However, despite many efforts and much progress, cell− cell fusion has remained elusive to our understanding. Along the life of the fusion pore, large conformational changes take place from the initial lipid bilayer bending, passing through the hemifusion intermediates, and ending with the formation of the first nascent fusion pore. In this sense, computer simulations are an ideal technique for describing such complex lipid remodeling at the molecular level. In this work, we studied the role played by the muscle-specific membrane protein Myomerger during the formation of the fusion pore. We have conducted μs length atomistic and coarse-grained molecular dynamics, together with free-energy calculations using ad hoc collective variables. Our results show that Myomerger favors the hemifusion diaphragm−stalk transition, reduces the nucleation−expansion energy difference, and promotes the formation of nonenlarging fusion pores.

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Section: Methodsmentioning

confidence: 99%

Myomerger Induces Membrane Hemifusion and Regulates Fusion Pore Expansion

Di Bartolo,

Caparotta,

Polo

et al. 2024

Biochemistry

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“…Besides, the 3D hopping via dissociation/reassociation can add another layer of computational difficulty in all-atom MD simulations. Because of this limitation, coarse-grained MD simulations have been used to investigate dynamic features or free energy profiles of various enzyme translations along DNA, providing biophysical insight into these translocation mechanisms. − Until now, all-atom MD simulation studies, however, have been mostly limited to free energy investigations of the 1D helical sliding without 3D hopping. − Despite recent advances in all-atom force fields − and novel simulation methods, − overall free energy landscapes describing the associative and dissociative transfers of enzymes at atomistic resolution have not been reported. For the computation of such free energy landscapes, robust enhanced sampling MD strategies are needed to overcome the pre-existing computational limitation and to fully explore proper 1D sliding and 3D hoping modes occurring through cycles of enzyme association/dissociation.…”

Section: Introductionmentioning

confidence: 99%

Three-State Diffusion Model of DNA Glycosylase Translocation along Stretched DNA as Revealed by Free Energy Landscapes at the All-Atom Level

Kim,

Pak

2024

J. Chem. Theory Comput.

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DNA glycosylases play key roles in the maintenance of genomic integrity. These enzymes effectively find rare damaged sites in DNA and participate in subsequent base excision repair. Single-molecule and ensemble experiments have revealed key aspects of this damage-site searching mechanism and the involvement of facilitated diffusion. In this study, we describe free energy landscapes of enzyme translocation along nonspecific DNA obtained using a fully atomistic molecular dynamics (MD) simulation of a well-known DNA glycosylase, human 8-oxoguanine DNA glycosylase 1 (hOGG1). Based on an analysis of simulated free energy profiles, we propose a three-state model for the damage-site searching mechanism. In the three states, named the L1, L2, and L3 states, the L1 state is a helical sliding mode in close contact with DNA, whereas the L2 state is a major-or minor-groove tracking mode in loose contact with DNA and the L3 state is a two-dimensional freely diffusing mode during which hOGG1 is somewhat removed from the DNA surface (∼24 Å away from the surface). This three-state model well describes key experimental findings obtained from single-molecule and ensemble experiments and provides a unified molecular picture of the DNA lesion-searching mechanism of hOGG1.

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When MELD Meets GaMD: Accelerating Biomolecular Landscape Exploration

Cited by 2 publications

References 60 publications

Myomerger Induces Membrane Hemifusion and Regulates Fusion Pore Expansion

Myomerger Induces Membrane Hemifusion and Regulates Fusion Pore Expansion

Three-State Diffusion Model of DNA Glycosylase Translocation along Stretched DNA as Revealed by Free Energy Landscapes at the All-Atom Level

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