scholarly journals MD Simulations on a Well-Built Docking Model Reveal Fine Mechanical Stability and Force-Dependent Dissociation of Mac-1/GPIbα Complex

2021 ◽  
Vol 8 ◽  
Author(s):  
Xiaoyan Jiang ◽  
Xiaoxi Sun ◽  
Jiangguo Lin ◽  
Yingchen Ling ◽  
Ying Fang ◽  
...  
Keyword(s):  
Molecular Dynamics ◽  
Molecular Basis ◽  
Mechanical Stability ◽  
Inflammatory Responses ◽  
Bond Number ◽  
Complex Model ◽  
Platelet Glycoprotein ◽  
Regulation Mechanism ◽  
Dissociation Probability ◽  
Docking Model

Interaction of leukocyte integrin macrophage-1 antigen (Mac-1) to platelet glycoprotein Ibα (GPIbα) is critical for platelet–leukocyte crosstalk in hemostasis and inflammatory responses to vessel injuries under hemodynamic environments. The mechano-regulation and its molecular basis for binding of Mac-1 to GPIbα remain unclear, mainly coming from the lack of crystal structure of the Mac-1/GPIbα complex. We herein built a Mac-1/GPIbα complex model through a novel computer strategy, which included a flexible molecular docking and system equilibrium followed by a “force-ramp + snapback” molecular dynamics (MD) simulation. With this model, a series of “ramp-clamp” steered molecular dynamics (SMD) simulations were performed to examine the GPIbα–Mac-1 interaction under various loads. The results demonstrated that the complex was mechano-stable for both the high rupture force (>250 pN) at a pulling velocity of 3 Å/ns and the conformational conservation under various constant tensile forces (≤75 pN); a catch-slip bond transition was predicted through the dissociation probability, examined with single molecular AFM measurements, reflected by the interaction energy and the interface H-bond number, and related to the force-induced allostery of the complex; besides the mutation-identified residues D222 and R218, the residues were also dominant in the binding of Mac-1 to GPIbα. This study recommended a valid computer strategy for building a likely wild-type docking model of a complex, provided a novel insight into the mechanical regulation mechanism and its molecular basis for the interaction of Mac-1 with GPIbα, and would be helpful for understanding the platelet–leukocyte interaction in hemostasis and inflammatory responses under mechano-microenvironments.

Molecular Basis of Iterative C–H Oxidation by TamI, a Multifunctional P450 Monooxygenase from the Tirandamycin Biosynthetic Pathway

2020 ◽  
Author(s):  
Sean A. Newmister ◽  
Kinshuk Raj Srivastava ◽  
Rosa V. Espinoza ◽  
Kersti Caddell Haatveit ◽  
Yogan Khatri ◽  
...  
Keyword(s):  
Molecular Dynamics ◽  
Molecular Dynamics Simulations ◽  
Molecular Basis ◽  
Hydrophobic Interactions ◽  
Cytochromes P450 ◽  
Targeted Mutagenesis ◽  
P450 Monooxygenase ◽  
Bond Functionalization ◽  
Dynamics Simulations

Biocatalysis offers an expanding and powerful strategy to construct and diversify complex molecules by C-H bond functionalization. Due to their high selectivity, enzymes have become an essential tool for C-H bond functionalization and offer complementary reactivity to small-molecule catalysts. Hemoproteins, particularly cytochromes P450, have proven effective for selective oxidation of unactivated C-H bonds. Previously, we reported the in vitro characterization of an oxidative tailoring cascade in which TamI, a multifunctional P450 functions co-dependently with the TamL flavoprotein to catalyze regio- and stereoselective hydroxylations and epoxidation to yield tirandamycin A and tirandamycin B. TamI follows a defined order including 1) C10 hydroxylation, 2) C11/C12 epoxidation, and 3) C18 hydroxylation. Here we present a structural, biochemical, and computational investigation of TamI to understand the molecular basis of its substrate binding, diverse reactivity, and specific reaction sequence. The crystal structure of TamI in complex with tirandamycin C together with molecular dynamics simulations and targeted mutagenesis suggest that hydrophobic interactions with the polyene chain of its natural substrate are critical for molecular recognition. QM/MM calculations and molecular dynamics simulations of TamI with variant substrates provided detailed information on the molecular basis of sequential reactivity, and pattern of regio- and stereo-selectivity in catalyzing the three-step oxidative cascade.<br>

scholarly journals Molecular Basis of Bcl-XL-p53 Interaction: Insights from Molecular Dynamics Simulations

PLoS ONE ◽  
2011 ◽  
Vol 6 (10) ◽  
pp. e26014 ◽  
Author(s):  
Nagakumar Bharatham ◽  
Seung-Wook Chi ◽  
Ho Sup Yoon
Keyword(s):  
Molecular Dynamics ◽  
Molecular Dynamics Simulations ◽  
Molecular Basis ◽  
Dynamics Simulations

Molecular dynamics simulation of geminal dicationic ionic liquids [Cn(mim)2][NTf2]2 – structural and dynamical properties

2018 ◽  
Vol 20 (1) ◽  
pp. 435-448 ◽  
Author(s):  
Majid Moosavi ◽  
Fatemeh Khashei ◽  
Elaheh Sedghamiz
Keyword(s):  
Molecular Dynamics ◽  
Ionic Liquids ◽  
Molecular Dynamics Simulation ◽  
Liquid Phase ◽  
Molecular Basis ◽  
Dynamics Simulation ◽  
Bulk Liquid ◽  
Fundamental Understanding ◽  
Dicationic Ionic Liquids ◽  
Dynamical Properties

The structural and dynamical properties of two dicationic ionic liquids, i.e. [Cn(mim)2][NTf2]2 with n = 3 and 5, have been studied to obtain a fundamental understanding of the molecular basis of the macroscopic and microscopic properties of the bulk liquid phase.

scholarly journals Molecular Dynamics Approaches Estimate the Binding Energy of HIV-1 Integrase Inhibitors and Correlate withIn VitroActivity

2011 ◽  
Vol 56 (1) ◽  
pp. 411-419 ◽  
Author(s):  
Barry C. Johnson ◽  
Mathieu Métifiot ◽  
Yves Pommier ◽  
Stephen H. Hughes
Keyword(s):  
Molecular Dynamics ◽  
Binding Energy ◽  
Foamy Virus ◽  
Complex Model ◽  
Integrase Inhibitors ◽  
Training Set ◽  
Viral Dna ◽  
Starting Point ◽  
Hiv 1

ABSTRACTThe design of novel integrase (IN) inhibitors has been aided by recent crystal structures revealing the binding mode of these compounds with a full-length prototype foamy virus (PFV) IN and synthetic viral DNA ends. Earlier docking studies relied on incomplete structures and did not include the contribution of the viral DNA to inhibitor binding. Using the structure of PFV IN as the starting point, we generated a model of the corresponding HIV-1 complex and developed a molecular dynamics (MD)-based approach that correlates with thein vitroactivities of novel compounds. Four well-characterized compounds (raltegravir, elvitegravir, MK-0536, and dolutegravir) were used as a training set, and the data for theirin vitroactivity against the Y143R, N155H, and G140S/Q148H mutants were used in addition to the wild-type (WT) IN data. Three additional compounds were docked into the IN-DNA complex model and subjected to MD simulations. All three gave interaction potentials within 1 standard deviation of values estimated from the training set, and the most active compound was identified. Additional MD analysis of the raltegravir- and dolutegravir-bound complexes gave internal and interaction energy values that closely match the experimental binding energy of a compound related to raltegravir that has similar activity. These approaches can be used to gain a deeper understanding of the interactions of the inhibitors with the HIV-1 intasome and to identify promising scaffolds for novel integrase inhibitors, in particular, compounds that retain activity against a range of drug-resistant mutants, making it possible to streamline synthesis and testing.

scholarly journals A Molecular Dynamics Study of the Effect of the Incidence Angle on the Dissociation Probability of H2 on Pt(111)

2011 ◽  
Vol 6 (3) ◽  
pp. 333-343
Author(s):  
Tetsuya KOIDO ◽  
Daigo ITO ◽  
Takashi TOKUMASU ◽  
Ko TOMARIKAWA ◽  
Shigeru YONEMURA
Keyword(s):  
Molecular Dynamics ◽  
Incidence Angle ◽  
Dissociation Probability
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