3,078 research outputs found
A detailed binding free energy study of 2 : 1 ligand–DNA complex formation by experiment and simulation
In 2004, we used NMR to solve the structure of the minor groove binder thiazotropsin A bound in a 2 : 1 complex to the DNA duplex, d(CGACTAGTCG)2. In this current work, we have combined theory and experiment to confirm the binding thermodynamics of this system. Molecular dynamics simulations that use polarizable or non-polarizable force fields with single and separate trajectory approaches have been used to explore complexation at the molecular level. We have shown that the binding process invokes large conformational changes in both the receptor and ligand, which is reflected by large adaptation energies. This is compensated for by the net binding free energy, which is enthalpy driven and entropically opposed. Such a conformational change upon binding directly impacts on how the process must be simulated in order to yield accurate results. Our MM-PBSA binding calculations from snapshots obtained from MD simulations of the polarizable force field using separate trajectories yield an absolute binding free energy (-15.4 kcal mol-1) very close to that determined by isothermal titration calorimetry (-10.2 kcal mol-1). Analysis of the major energy components reveals that favorable non-bonded van der Waals and electrostatic interactions contribute predominantly to the enthalpy term, whilst the unfavorable entropy appears to be driven by stabilization of the complex and the associated loss of conformational freedom. Our results have led to a deeper understanding of the nature of side-by-side minor groove ligand binding, which has significant implications for structure-based ligand development
The Interplay between Chemistry and Mechanics in the Transduction of a Mechanical Signal into a Biochemical Function
There are many processes in biology in which mechanical forces are generated.
Force-bearing networks can transduce locally developed mechanical signals very
extensively over different parts of the cell or tissues. In this article we
conduct an overview of this kind of mechanical transduction, focusing in
particular on the multiple layers of complexity displayed by the mechanisms
that control and trigger the conversion of a mechanical signal into a
biochemical function. Single molecule methodologies, through their capability
to introduce the force in studies of biological processes in which mechanical
stresses are developed, are unveiling subtle intertwining mechanisms between
chemistry and mechanics and in particular are revealing how chemistry can
control mechanics. The possibility that chemistry interplays with mechanics
should be always considered in biochemical studies.Comment: 50 pages, 18 figure
Examination of Molecular Recognition in Protein-Ligand Interactions
This dissertation is a compilation of two main projects that were investigated during my thesis research. The first project was a prospective study which identified and characterized drug-like inhibitors of a prototype of bacterial two-component signal transduction response regulator using computational and experimental methods. The second project was the development and validation of a scoring function, PHOENIX, derived using high-resolution structures and calorimetry measurements to predict binding affinities of protein-ligand interactions. Collectively, my thesis research aimed to better understand the underlying driving forces and principles which govern molecular recognition and molecular design. A prospective study coupled computational predictions with experimental validation resulted in the discovery of first-in-class inhibitors targeting a signal transduction module important for bacterial virulence. Development and validation of the PHOENIX scoring function for binding affinity prediction derived using high-resolution structures and calorimetry measurements should guide future molecular recognition studies and endeavors in computer-aided molecular design. To request for an electronic copy of this dissertation, please email the author: yattang at gmail dot com)
Applying Computational Scoring Functions to Assess Biomolecular Interactions in Food Science: Applications to the Estrogen Receptors
During the last decade, computational methods, which were for the most part developed to study protein-ligand interactions and especially to discover, design and develop drugs by and for medicinal chemists, have been successfully applied in a variety of food science applications [1,2]. It is now clear, in fact, that drugs and nutritional molecules behave in the same way when binding to a macromolecular target or receptor, and that many of the approaches used so extensively in medicinal chemistry can be easily transferred to the fields of food science. For instance, nuclear receptors are common targets for a number of drug molecules and could be, in the same way, affected by the interaction with food or food-like molecules. Thus, key computational medicinal chemistry methods like molecular dynamics can be used to decipher protein flexibility and to obtain stable models for docking and scoring in food-related studies, and virtual screening is increasingly being applied to identify molecules with potential to act as endocrine disruptors, food mycotoxins, and new nutraceuticals [3,4,5]. All of these methods and simulations are based on protein-ligand interaction phenomena, and represent the basis for any subsequent modification of the targeted receptor's or enzyme's physiological activity. We describe here the energetics of binding of biological complexes, providing a survey of the most common and successful algorithms used in evaluating these energetics, and we report case studies in which computational techniques have been applied to food science issues. In particular, we explore a handful of studies involving the estrogen receptors for which we have a long-term interest
Advances and Challenges in Protein-Ligand Docking
Molecular docking is a widely-used computational tool for the study of molecular recognition, which aims to predict the binding mode and binding affinity of a complex formed by two or more constituent molecules with known structures. An important type of molecular docking is protein-ligand docking because of its therapeutic applications in modern structure-based drug design. Here, we review the recent advances of protein flexibility, ligand sampling, and scoring functions—the three important aspects in protein-ligand docking. Challenges and possible future directions are discussed in the Conclusion
Binding Modes of Peptidomimetics Designed to Inhibit STAT3
STAT3 is a transcription factor that has been found to be constitutively activated in a number of human cancers.
Dimerization of STAT3 via its SH2 domain and the subsequent translocation of the dimer to the nucleus leads to
transcription of anti-apoptotic genes. Prevention of the dimerization is thus an attractive strategy for inhibiting the activity
of STAT3. Phosphotyrosine-based peptidomimetic inhibitors, which mimic pTyr-Xaa-Yaa-Gln motif and have strong to weak
binding affinities, have been previously investigated. It is well-known that structures of protein-inhibitor complexes are
important for understanding the binding interactions and designing stronger inhibitors. Experimental structures of
inhibitors bound to the SH2 domain of STAT3 are, however, unavailable. In this paper we describe a computational study
that combined molecular docking and molecular dynamics to model structures of 12 peptidomimetic inhibitors bound to
the SH2 domain of STAT3. A detailed analysis of the modeled structures was performed to evaluate the characteristics of the
binding interactions. We also estimated the binding affinities of the inhibitors by combining MMPB/GBSA-based energies
and entropic cost of binding. The estimated affinities correlate strongly with the experimentally obtained affinities.
Modeling results show binding modes that are consistent with limited previous modeling studies on binding interactions
involving the SH2 domain and phosphotyrosine(pTyr)-based inhibitors. We also discovered a stable novel binding mode
that involves deformation of two loops of the SH2 domain that subsequently bury the C-terminal end of one of the stronger
inhibitors. The novel binding mode could prove useful for developing more potent inhibitors aimed at preventing
dimerization of cancer target protein STAT3
Variational Methods for Biomolecular Modeling
Structure, function and dynamics of many biomolecular systems can be
characterized by the energetic variational principle and the corresponding
systems of partial differential equations (PDEs). This principle allows us to
focus on the identification of essential energetic components, the optimal
parametrization of energies, and the efficient computational implementation of
energy variation or minimization. Given the fact that complex biomolecular
systems are structurally non-uniform and their interactions occur through
contact interfaces, their free energies are associated with various interfaces
as well, such as solute-solvent interface, molecular binding interface, lipid
domain interface, and membrane surfaces. This fact motivates the inclusion of
interface geometry, particular its curvatures, to the parametrization of free
energies. Applications of such interface geometry based energetic variational
principles are illustrated through three concrete topics: the multiscale
modeling of biomolecular electrostatics and solvation that includes the
curvature energy of the molecular surface, the formation of microdomains on
lipid membrane due to the geometric and molecular mechanics at the lipid
interface, and the mean curvature driven protein localization on membrane
surfaces. By further implicitly representing the interface using a phase field
function over the entire domain, one can simulate the dynamics of the interface
and the corresponding energy variation by evolving the phase field function,
achieving significant reduction of the number of degrees of freedom and
computational complexity. Strategies for improving the efficiency of
computational implementations and for extending applications to coarse-graining
or multiscale molecular simulations are outlined.Comment: 36 page
Assessment of Hydration Thermodynamics at Protein Interfaces with Grid Cell Theory
Molecular
dynamics simulations have been analyzed with the Grid
Cell Theory (GCT) method to spatially resolve the binding enthalpies
and entropies of water molecules at the interface of 17 structurally
diverse proteins. Correlations between computed energetics and structural
descriptors have been sought to facilitate the development of simple
models of protein hydration. Little correlation was found between
GCT-computed binding enthalpies and continuum electrostatics calculations.
A simple count of contacts with functional groups in charged amino
acids correlates well with enhanced water stabilization, but the stability
of water near hydrophobic and polar residues depends markedly on its
coordination environment. The positions of X-ray-resolved water molecules
correlate with computed high-density hydration sites, but many unresolved
waters are significantly stabilized at the protein surfaces. A defining
characteristic of ligand-binding pockets compared to nonbinding pockets
was a greater solvent-accessible volume, but average water thermodynamic
properties were not distinctive from other interfacial regions. Interfacial
water molecules are frequently stabilized by enthalpy and destabilized
entropy with respect to bulk, but counter-examples occasionally occur.
Overall detailed inspection of the local coordinating environment
appears necessary to gauge the thermodynamic stability of water in
protein structures
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