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Perturbation Approaches for Exploring Protein Binding Site Flexibility to Predict Transient Binding Pockets

Abstract

Not specified

Authors: Daria B. Kokh, Paul Czodrowski, Friedrich Rippmann, Rebecca C. Wade

Date Published: 2016

Publication Type: Journal

Three steps to Gold: Mechanism of protein adsorption to a gold surface revealed by Brownian and molecular dynamics simulations

Abstract

Not specified

Authors: M. Ozboyaci, D. B. Kokh, R. C. Wade

Date Published: 2016

Publication Type: Journal

Dynathor: Dynamics of the Complex of Cytochrome P450 and Cytochrome P450 Reductase in a Phospholipid Bilayer

Abstract

Not specified

Authors: Xiaofeng Yu, Daria B. Kokh, Prajwal Nandekar, Ghulam Mustafa, Stefan Richter, Rebecca C. Wade

Date Published: 2016

Publication Type: InCollection

Modeling and simulation of protein–surface interactions: achievements and challenges

Abstract (Expand)

Understanding protein–inorganic surface interactions is central to the rational design of new tools in biomaterial sciences, nanobiotechnology and nanomedicine. Although a significant amount of … experimental research on protein adsorption onto solid substrates has been reported, many aspects of the recognition and interaction mechanisms of biomolecules and inorganic surfaces are still unclear. Theoretical modeling and simulations provide complementary approaches for experimental studies, and they have been applied for exploring protein–surface binding mechanisms, the determinants of binding specificity towards different surfaces, as well as the thermodynamics and kinetics of adsorption. Although the general computational approaches employed to study the dynamics of proteins and materials are similar, the models and force-fields (FFs) used for describing the physical properties and interactions of material surfaces and biological molecules differ. In particular, FF and water models designed for use in biomolecular simulations are often not directly transferable to surface simulations and vice versa. The adsorption events span a wide range of time- and length-scales that vary from nanoseconds to days, and from nanometers to micrometers, respectively, rendering the use of multi-scale approaches unavoidable. Further, changes in the atomic structure of material surfaces that can lead to surface reconstruction, and in the structure of proteins that can result in complete denaturation of the adsorbed molecules, can create many intermediate structural and energetic states that complicate sampling. In this review, we address the challenges posed to theoretical and computational methods in achieving accurate descriptions of the physical, chemical and mechanical properties of protein-surface systems. In this context, we discuss the applicability of different modeling and simulation techniques ranging from quantum mechanics through all-atom molecular mechanics to coarse-grained approaches. We examine uses of different sampling methods, as well as free energy calculations. Furthermore, we review computational studies of protein–surface interactions and discuss the successes and limitations of current approaches.

Authors: Musa Ozboyaci, Daria B. Kokh, Stefano Corni, Rebecca C. Wade

Date Published: 2016

Publication Type: Journal

Ligand tunnels in T. brucei and human CYP51: Insights for parasite-specific drug design

Abstract (Expand)

AbstractBackground Cytochrome {P450} sterol 14α-demethylase (CYP51) is an essential enzyme for sterol biosynthesis and a target for anti-parasitic drug design. However, the design of parasite-specific … drugs that inhibit parasitic {CYP51} without severe side effects remains challenging. The active site of {CYP51} is situated in the interior of the protein. Here, we characterize the potential ligand egress routes and mechanisms in Trypanosoma brucei and human {CYP51} enzymes. Methods We performed Random Acceleration Molecular Dynamics simulations of the egress of four different ligands from the active site of models of soluble and membrane-bound T. brucei {CYP51} and of soluble human CYP51. Results In the simulations, tunnel 2 f, which leads to the membrane, was found to be the predominant ligand egress tunnel for all the ligands studied. Tunnels S, 1 and W, which lead to the cytosol, were also used in T. brucei CYP51, whereas tunnel 1 was the only other tunnel used significantly in human CYP51. The common tunnels found previously in other {CYPs} were barely used. The ligand egress times were shorter for human than T. brucei CYP51, suggesting lower barriers to ligand passage. Two gating residues, {F105} and M460, in T. brucei {CYP51} that modulate the opening of tunnels 2 f and S were identified. Conclusions Although the main egress tunnel was the same, differences in the tunnel-lining residues, ligand passage and tunnel usage were found between T. brucei and human CYP51s. General Significance The results provide a basis for the design of selective anti-parasitic agents targeting the ligand tunnels.

Authors: Xiaofeng Yu, Prajwal Nandekar, Ghulam Mustafa, Vlad Cojocaru, Galina I. Lepesheva, Rebecca C. Wade

Date Published: 2016

Publication Type: Journal

Modeling and Simulation of Protein-Surface Interactions

Abstract

Not specified

Author: Musa Ozboyaci

Date Published: 2016

Publication Type: Doctoral Thesis

Case Study of Human Growth Hormone Interactions by Brownian Dynamics Simulation

Abstract

Not specified

Author: Astrid Stubbusch

Date Published: 2016

Publication Type: Bachelor's Thesis

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