skip to main content
US FlagAn official website of the United States government
dot gov icon
Official websites use .gov
A .gov website belongs to an official government organization in the United States.
https lock icon
Secure .gov websites use HTTPS
A lock ( lock ) or https:// means you've safely connected to the .gov website. Share sensitive information only on official, secure websites.

Explore Research Products in the PAR
It may take a few hours for recently added research products to appear in PAR search results.


Title: Role of Resultant Dipole Moment in Mechanical Dissociation of Biological Complexes
Protein-peptide interactions play essential roles in many cellular processes and their structural characterization is the major focus of current experimental and theoretical research. Two decades ago, it was proposed to employ the steered molecular dynamics (SMD) to assess the strength of protein-peptide interactions. The idea behind using SMD simulations is that the mechanical stability can be used as a promising and an efficient alternative to computationally highly demanding estimation of binding affinity. However, mechanical stability defined as a peak in force-extension profile depends on the choice of the pulling direction. Here we propose an uncommon choice of the pulling direction along resultant dipole moment (RDM) vector, which has not been explored in SMD simulations so far. Using explicit solvent all-atom MD simulations, we apply SMD technique to probe mechanical resistance of ligand-receptor system pulled along two different vectors. A novel pulling direction—when ligand unbinds along the RDM vector—results in stronger forces compared to commonly used ligand unbinding along center of masses vector. Our observation that RDM is one of the factors influencing the mechanical stability of protein-peptide complex can be used to improve the ranking of binding affinities by using mechanical stability as an effective scoring function.  more » « less
Award ID(s):
1661391
PAR ID:
10095901
Author(s) / Creator(s):
; ; ; ;
Date Published:
Journal Name:
Molecules
Volume:
23
Issue:
8
ISSN:
1420-3049
Page Range / eLocation ID:
1995
Format(s):
Medium: X
Sponsoring Org:
National Science Foundation
More Like this
  1. ; ; ; ; ; (, Biophysical Journal)
    The actin filament network is in part remodeled by the action of a family of filament severing proteins that are responsible for modulating the ratio between monomeric and filamentous actin. Recent work on the protein Actophorin from the amoeba Acanthamoeba castellani identified a series of site directed mutations that increase the thermal stability of the protein by 22 ◦C. Here, we expand this observation by showing that the mutant protein is also significantly stable to both equilibrium and kinetic chemical denaturation, and employ computer simulations to account for the increase in thermal or chemical stability through an accounting of atomic-level interactions. Specifically, the potential of mean force (PMF) can be obtained from steered molecular dynamics (SMD) simulations in which a protein is unfolded. However, SMD can be inefficient for large proteins as they require large solvent boxes, and computationally expensive as they require increasingly many SMD trajectories to converge the PMF. Adaptive steered molecular dynamics (ASMD) overcomes the second of these limitations by steering the particle in stages, which allows for convergence of the PMF using fewer trajectories compared to SMD. Use of the telescoping water scheme within ASMD partially overcomes the first of these limitations by reducing the number of waters at each stage to only those needed to solvate the structure within a given stage. In the PMFs obtained from ASMD, the work of unfolding Acto-2 was found to be higher than the Acto-WT by approximately 120 kCal/mol and reflects the increased stability seen in the chemical denaturation experiments. The evolution of the average number of hydrogen bonds andnumber of salt bridges during the pulling process provides a mechanistic view of the structural changes of the Actophorin protein as it is unfolded, and how it is affected by the mutation in concert with the energetics reported through the PMF. 
    more » « less
  2. ; ; ; ; (, Philosophical Transactions of the Royal Society A: Mathematical, Physical and Engineering Sciences)
    Integrin, as a mechanotransducer, establishes the mechanical reciprocity between the extracellular matrix (ECM) and cells at integrin-mediated adhesion sites. This study used steered molecular dynamics (SMD) simulations to investigate the mechanical responses of integrinαvβ3with and without 10th type III fibronectin (FnIII10) binding for tensile, bending and torsional loading conditions. The ligand-binding integrin confirmed the integrin activation during equilibration and altered the integrin dynamics by changing the interface interaction between β-tail, hybrid and epidermal growth factor domains during initial tensile loading. The tensile deformation in integrin molecules indicated that fibronectin ligand binding modulates its mechanical responses in the folded and unfolded conformation states. The bending deformation responses of extended integrin models reveal the change in behaviour of integrin molecules in the presence of Mn2+ion and ligand based on the application of force in the folding and unfolding directions of integrin. Furthermore, these SMD simulation results were used to predict the mechanical properties of integrin underlying the mechanism of integrin-based adhesion. The evaluation of integrin mechanics provides new insights into understanding the mechanotransmission (force transmission) between cells and ECM and contributes to developing an accurate model for integrin-mediated adhesion. This article is part of a discussion meeting issue ‘Supercomputing simulations of advanced materials’. 
    more » « less
  3. ; ; ; ; ; ; ; (, WIREs Computational Molecular Science)
    Abstract Gaussian accelerated molecular dynamics (GaMD) is a robust computational method for simultaneous unconstrained enhanced sampling and free energy calculations of biomolecules. It works by adding a harmonic boost potential to smooth biomolecular potential energy surface and reduce energy barriers. GaMD greatly accelerates biomolecular simulations by orders of magnitude. Without the need to set predefined reaction coordinates or collective variables, GaMD provides unconstrained enhanced sampling and is advantageous for simulating complex biological processes. The GaMD boost potential exhibits a Gaussian distribution, thereby allowing for energetic reweighting via cumulant expansion to the second order (i.e., “Gaussian approximation”). This leads to accurate reconstruction of free energy landscapes of biomolecules. Hybrid schemes with other enhanced sampling methods, such as the replica‐exchange GaMD (rex‐GaMD) and replica‐exchange umbrella sampling GaMD (GaREUS), have also been introduced, further improving sampling and free energy calculations. Recently, new “selective GaMD” algorithms including the Ligand GaMD (LiGaMD) and Peptide GaMD (Pep‐GaMD) enabled microsecond simulations to capture repetitive dissociation and binding of small‐molecule ligands and highly flexible peptides. The simulations then allowed highly efficient quantitative characterization of the ligand/peptide binding thermodynamics and kinetics. Taken together, GaMD and its innovative variants are applicable to simulate a wide variety of biomolecular dynamics, including protein folding, conformational changes and allostery, ligand binding, peptide binding, protein–protein/nucleic acid/carbohydrate interactions, and carbohydrate/nucleic acid interactions. In this review, we present principles of the GaMD algorithms and recent applications in biomolecular simulations and drug design. This article is categorized under:Structure and Mechanism > Computational Biochemistry and BiophysicsMolecular and Statistical Mechanics > Molecular Dynamics and Monte‐Carlo MethodsMolecular and Statistical Mechanics > Free Energy Methods 
    more » « less
  4. ; ; (, bioRxiv)
    Endocannabinoids are naturally occurring lipid-like molecules that bind to cannabinoid receptors (CB1and CB2) and regulate many of human bodily functions via the endocannabinoid system. There is a tremendous interest in developing selective drugs that target the CB receptors. However, the biophysical mechanisms responsible for the subtype selectivity for endocannbinoids have not been established. Recent experimental structures of CB receptors show that endocannbinoids potentially bind via membrane using the lipid access channel in the transmembrane region of the receptors. Furthermore, the N-terminus of the receptor could move in and out of the binding pocket thereby modulating both the pocket volume and its residue composition. On the basis of these observations, we propose two hypothesis to explain the selectivity of the endocannabinoid, anandamide for CB1receptor. First, the selectivity arises from distinct enthalpic ligand-protein interactions along the ligand binding pathway formed due to the movement of N-terminus and subsequent shifts in the binding pocket composition. Second, selectivity arises from the volumetric differences in the binding pocket allowing for differences in ligand conformational entropy. To quantitatively test these hypothesis, we perform extensive molecular dynamics simulations (∼0.9 milliseconds) along with Markov state modeling and deep learning-based VAMPnets to provide an interpretable characterization of the anandamide binding process to cannabinoid receptors and explain its selectivity for CB1. Our findings reveal that the distinct N-terminus positions along lipid access channels between TM1 and TM7 lead to different binding mechanisms and interactions between anandamide and the binding pocket residues. To validate the critical stabilizing interactions along the binding pathway, relative free energy calculations of anandamide analogs are used. Moreover, the larger CB2pocket volume increases the entropic effects of ligand binding by allowing higher ligand fluctuations but reduced stable interactions. Therefore, the opposing enthalpy and entropy effects between the receptors shape the endocannabinoid selectivity. Overall, the CB1selectivity of anandamide is explained by the dominant enthalpy contributions due to ligand-protein interactions in stable binding poses. This study shed lights on potential selectivity mechanisms for endocannabinoids that would aid in the discovery of CB selective drugs 
    more » « less
  5. ; ; ; (, Proteins: Structure, Function, and Bioinformatics)
    Abstract SH2B1 is a multidomain protein that serves as a key adaptor to regulate numerous cellular events, such as insulin, leptin, and growth hormone signaling pathways. Many of these protein‐protein interactions are mediated by the SH2 domain of SH2B1, which recognizes ligands containing a phosphorylated tyrosine (pY), including peptides derived from janus kinase 2, insulin receptor, and insulin receptor substrate‐1 and −2. Specificity for the SH2 domain of SH2B1 is conferred in these ligands either by a hydrophobic or an acidic side chain at the +3 position C‐terminal to the pY. This specificity for chemically disparate species suggests that SH2B1 relies on distinct thermodynamic or structural mechanisms to bind to peptides. Using binding and structural strategies, we have identified unique thermodynamic signatures for each peptide binding mode, and several SH2B1 residues, including K575 and R578, that play distinct roles in peptide binding. The high‐resolution structure of the SH2 domain of SH2B1 further reveals conformationally plastic protein loops that may contribute to the ability of the protein to recognize dissimilar ligands. Together, numerous hydrophobic and electrostatic interactions, in addition to backbone conformational flexibility, permit the recognition of diverse peptides by SH2B1. An understanding of this expanded peptide recognition will allow for the identification of novel physiologically relevant SH2B1/peptide interactions, which can contribute to the design of obesity and diabetes pharmaceuticals to target the ligand‐binding interface of SH2B1 with high specificity. 
    more » « less
  • Citation Formats
  • MLA
  • APA
  • Chicago
  • BibTeX
  • Save / Share this Record
  • Send to Email