Association and dissociation simulations of bio molecular complex using parallel cascade selection molecular dynamics
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Association and dissociation simulations of bio molecular complex using parallel cascade selection molecular dynamics
Doctoral ThesisAssociation and dissociation simulations of bio-molecular complex using parallel cascade selection molecular dynamicsThe University of Association and dissociation simulations of bio molecular complex using parallel cascade selection molecular dynamics Tokyo Greduate Shool of Frontier SciencesDepartment of Computational Biology and Medical SciencesTran Phuoc DuyDoctoral ThesisAssociation and dissociation simulations of bio-molecular complex using parallel cascade selection molecular dynamicsy XỴIn memory of my fatherTo my mother and my sister Wit Association and dissociation simulations of bio molecular complex using parallel cascade selection molecular dynamics h eternal love and appreciationAbstractSampling conformations of protein complexes during association and dissociation processes is a crucial siep toAssociation and dissociation simulations of bio molecular complex using parallel cascade selection molecular dynamics
estimate the binding free energy and other kinetic properties from association dissociation pathways. This is a challenging problem for the classical Doctoral ThesisAssociation and dissociation simulations of bio-molecular complex using parallel cascade selection molecular dynamicsThe University of Association and dissociation simulations of bio molecular complex using parallel cascade selection molecular dynamics chniques play an important role to generate sufficient data for the free energy analysis. For example. Steered Molecular Dynamics (SMD) with Umbrella Sampling (US) [Ramirez et al., Methods Enzymol. (2016)], Replica Exchange Umbrella Sampling (REUS) [Sugita et al.. J. Chem. Phys (2000)]. Targeted MD Association and dissociation simulations of bio molecular complex using parallel cascade selection molecular dynamics (TMD) [Schlitter et al.. J. Mol. Graph. (1994)]. Parallel Cascade Selection Molecular Dynamics (PaCS-MD) [Harada and Kitao, J. Chem Phys. (2011)] andAssociation and dissociation simulations of bio molecular complex using parallel cascade selection molecular dynamics
other methods not listed here are used for this purpose. Recently, Yamashita and Fujitani showed that protein structures were distorted when dissociatDoctoral ThesisAssociation and dissociation simulations of bio-molecular complex using parallel cascade selection molecular dynamicsThe University of Association and dissociation simulations of bio molecular complex using parallel cascade selection molecular dynamics h led overestimation of the potential of mean force (PMF) with the following US. This can be considered as the artifact caused by SMD. In contrast to SMD. PaCS-MD performs conformational sampling by cycles of distinct multiple Molecular Dynamics (MD) simulations without applying any bias force to th Association and dissociation simulations of bio molecular complex using parallel cascade selection molecular dynamics e system. It enhances the sampling by selecting the MD snapshots closest to the destination state and by restarting the MD simulations from the selectAssociation and dissociation simulations of bio molecular complex using parallel cascade selection molecular dynamics
ed snapshots with the velocity rerandomization. PaCS-MD was shown to be very successful in efficient sampling of protein domain motions. Here in this Doctoral ThesisAssociation and dissociation simulations of bio-molecular complex using parallel cascade selection molecular dynamicsThe University of Association and dissociation simulations of bio molecular complex using parallel cascade selection molecular dynamics glucosamine (tnNAG). from hen egg white lysozyme (LYZ) very efficiently. We performed PaCS-MD trials with 3 different simulation settings: PaCS-MD10 01 (ten 0 1 ns MDs per cycle). PaCS-MD100 0 1 (hundred 0.1 ns MDs) and PaCS-MD101 (ten 1.0 ns MDs). We found that PaCS-MD is 5 times faster than SMD. I Association and dissociation simulations of bio molecular complex using parallel cascade selection molecular dynamics n combination with Markov State Model (MSM). we calculated the binding free energy directly from theiiPaCS-MD trajectories. In comparison, binding freAssociation and dissociation simulations of bio molecular complex using parallel cascade selection molecular dynamics
e energy was also calculated by the analysis of SMD trajectories using the Jarzynski equality [Jarzynski., Phys. Rev. Lett. (1997)]. Although SMD JarzDoctoral ThesisAssociation and dissociation simulations of bio-molecular complex using parallel cascade selection molecular dynamicsThe University of Association and dissociation simulations of bio molecular complex using parallel cascade selection molecular dynamics of the number of replicas, the length of each MD. the velocity rerandomization. and the selection of snapshots on PaCS-MD sampling. We found that the increase of the number of replicas reduced the number of cycles required for dissociation because the probability of observing rare events is proport Association and dissociation simulations of bio molecular complex using parallel cascade selection molecular dynamics ional to the number of replicas. The velocity re-randomization enhances the sampling in the bound state as it acts as a perturbation to raise the occuAssociation and dissociation simulations of bio molecular complex using parallel cascade selection molecular dynamics
rrence of rare events (dissociation).We next applied PaCS-MD to the dissociation of MDM2 protein and transactivation domain of p53 (TAD-p53). Binding Doctoral ThesisAssociation and dissociation simulations of bio-molecular complex using parallel cascade selection molecular dynamicsThe University of Association and dissociation simulations of bio molecular complex using parallel cascade selection molecular dynamics lt is more accurate than the value calculated by the MMGBSA method. 68.2 kJ/mol [Dastidar et al.. JACS (2008)]. We found the calculated binding free energy for each trial is strongly dependent on the dissociation pathway of TAD-p53, which is related to the dissociation of the key residues PHE19 and Association and dissociation simulations of bio molecular complex using parallel cascade selection molecular dynamics TRP23 of TAD-p53 involved in n-7t stacking interactions between TAD-p53 and MDM2.We also employed PaCS-MD for simulating association and dissociationAssociation and dissociation simulations of bio molecular complex using parallel cascade selection molecular dynamics
process of MDM2 TAD-p53. which can be considered as a flexible-body docking simulation We used the switching condition between the dissociation and asDoctoral ThesisAssociation and dissociation simulations of bio-molecular complex using parallel cascade selection molecular dynamicsThe University of Association and dissociation simulations of bio molecular complex using parallel cascade selection molecular dynamics mulation. When the inter COM distance between MDM2 and TAD-p53 reaches 2.0 nm longer than the last switching point, the association simulation will start. We performed 274 cycles of PaCS-MD and examined whether generated structures of TAD-p53 and MDM2 complex are similar to the crystal complex struc Association and dissociation simulations of bio molecular complex using parallel cascade selection molecular dynamics ture and found that the minimum RMSD was 0.429 nm. In addition. TAD-p53 could bind to the correct binding interface without the guiding force. We furtAssociation and dissociation simulations of bio molecular complex using parallel cascade selection molecular dynamics
her examined 4 representative structures selected from all the bound conformations. Although the two key 7T-7C stacking interactions were not formed iDoctoral ThesisAssociation and dissociation simulations of bio-molecular complex using parallel cascade selection molecular dynamicsThe University of Association and dissociation simulations of bio molecular complex using parallel cascade selection molecular dynamics the bound conformation without priorknowledge of the crystal structure, we examined if the conformation similar to the correct bound conformation can be identified as the lowest free energy structure. We built MSM based on the trajectories of distance RMSD (dRMSD) from the initial conformation of M Association and dissociation simulations of bio molecular complex using parallel cascade selection molecular dynamics DM2 TAD-p53 in the unbound state and calculated the Potential of Mean Force (PMF). We found that dRMSD of the lowest PMF position was 4.21 ntn, whichAssociation and dissociation simulations of bio molecular complex using parallel cascade selection molecular dynamics
the corresponding structure was identical to the structure with the lowest interface RMSD from the crystal structure. Therefore, we can select the besDoctoral ThesisAssociation and dissociation simulations of bio-molecular complex using parallel cascade selection molecular dynamicsThe University of Association and dissociation simulations of bio molecular complex using parallel cascade selection molecular dynamics plied to bio-molecular complexes and is highly suitable for distributed computing. Overall. PaCS-MD IS faster in computational time than the other biased sampling techniques. We are currently making an effort to apply PaCS-MD for reducing total simulation lime of flexible-body docking simulation.iv Association and dissociation simulations of bio molecular complex using parallel cascade selection molecular dynamics Doctoral ThesisAssociation and dissociation simulations of bio-molecular complex using parallel cascade selection molecular dynamicsThe University ofGọi ngay
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