Knowledge-based potentials for proteins

Sippl, Manfred J.

doi:10.1016/0959-440x(95)80081-6

Cited by 582 publications

(429 citation statements)

References 52 publications

Supporting

Mentioning

425

Contrasting

Order By: Relevance

“…Thornton, 1996). Pair additivity is usually assumed in calculating the total energy or score: the energy is the sum of the solvation and interaction energies of individual and pairs of residues (Sippl, 1995).…”

mentioning

confidence: 99%

“…The molecular surface and the solvent-accessible surface at the barrier are indicated schematically in Figure 3; the molecular surface is at a maximum because of the extended solvent-excluded region between the methanes, whereas the solvent-accessible surface is considerably less than that of the fully separated solutes (Wood & Thompson, 1990;Jackson & Sternberg, 1994). Simple potential functions used in protein folding studies often assume pair additivity of interactions between nonpolar groups (Sippl, 1995). To investigate potential many-body interactions, we simulated the formation of a trimer of methane molecules.…”

mentioning

confidence: 99%

See 1 more Smart Citation

A desolvation barrier to hydrophobic cluster formation may contribute to the rate‐limiting step in protein folding

1997

View full text Add to dashboard Cite

To gain insight into the free energy changes accompanying protein hydrophobic core formation, we have used computer simulations to study the formation of small clusters of nonpolar solutes in water. A barrier to association is observed at the largest solute separation that does not allow substantial solvent penetration. The barrier reflects an effective increase in the size of the cavity occupied by the expanded but water-excluding cluster relative to both the close-packed cluster and the fully solvated separated solutes; a similar effect may contribute to the barrier to protein foldinghnfolding. Importantly for the simulation of protein folding without explicit solvent, we find that the interactions between nonpolar solutes of varying size and number can be approximated by a linear function of the molecular surface, but not the solvent-accessible surface of the solutes. Comparison of the free energy of cluster formation to that of dimer formation suggests that the assumption of pair additivity implicit in current protein database derived potentials may be in error. Keywords: hydrophobic interaction; potential of mean force; protein foldingThe hydrophobic interaction is extremely important in the folding and stabilization of proteins (Kauzmann, 1959;Dill, 1990), but is relatively poorly understood. In spite of this poor understanding, computer modeling of protein folding has developed substantially over the past IO years. One approach is to simulate protein folding in the presence of explicitly modeled water molecules, which, depending upon the accuracy of the water model, should at least in part reproduce the hydrophobic interaction. Molecular dynamics simulations with an explicit solvent model have provided valuable insights into possible foldinghnfolding trajectories (Daggett & Levitt, 1994;Karplus & Sali, 1995). However, because of the complexity of the processes being simulated and the absence of an obvious reaction coordinate, most studies have focused on qualitative features of the trajectories and not sought to calculate free energy changes (the study of Brooks and Boczko [I9951 is an exception). A second approach avoids the complexity and high computational demands of simulations with hundreds of explicit water molecules by deriving effective potentials from the distribution of amino acid residues in known protein structures (reviewed in Jones & Thornton, 1996). Although not modeled explicitly, the hydrophobic interaction dominates such "knowledge-based' potentials. These relationships are not true interaction potentials in a rigorous sense, but they have been extremely useful in a wide variety of applications, including protein fold recognition (Jones &

show abstract

mentioning

confidence: 99%

mentioning

confidence: 99%

A desolvation barrier to hydrophobic cluster formation may contribute to the rate‐limiting step in protein folding

1997

View full text Add to dashboard Cite

show abstract

“…The energy functions of these models are defined in various ways, with physicsbased potentials using physical relations specified between atoms (or coarser united atom representations) while statistical potentials infer relations from the examination of a large number of structures gathered in a structural database. Statisticsbased energy functions are also referred to as knowledgebased (Sippl 1995). A combination of physics-based models and native structure-based models have been used to investigate protein-protein (Ganguly et al 2012;Kim and Hummer 2008;Okazaki et al 2012), protein-DNA Vuzman et al 2010), and protein receptor-small compound association/dissociation mechanisms (Negami et al 2014).…”

Section: Future Perspective Of Enhanced Sampling Methodsmentioning

confidence: 99%

Enhanced sampling simulations to construct free-energy landscape of protein–partner substrate interaction

2016

View full text Add to dashboard Cite

Molecular dynamics (MD) simulations using allatom and explicit solvent models provide valuable information on the detailed behavior of protein-partner substrate binding at the atomic level. As the power of computational resources increase, MD simulations are being used more widely and easily. However, it is still difficult to investigate the thermodynamic properties of protein-partner substrate binding and protein folding with conventional MD simulations. Enhanced sampling methods have been developed to sample conformations that reflect equilibrium conditions in a more efficient manner than conventional MD simulations, thereby allowing the construction of accurate free-energy landscapes. In this review, we discuss these enhanced sampling methods using a series of case-by-case examples. In particular, we review enhanced sampling methods conforming to trivial trajectory parallelization, virtual-system coupled multicanonical MD, and adaptive lambda square dynamics. These methods have been recently developed based on the existing method of multicanonical MD simulation. Their applications are reviewed with an emphasis on describing their practical implementation. In our concluding remarks we explore extensions of the enhanced sampling methods that may allow for even more efficient sampling.

show abstract

“…The stereochemical quality of the protein model is evaluated by the phi (Φ) and psi (ψ) angles of amino acids in Ramachandran plot using PROCHECK [40,41]. The ProSA server is used to assess the quality of the model based on the statistical analysis of all the available protein structures in PDB with the same sequence length [42]. The ProSA server gives the z-score that indicates an overall model quality and ProSA energy profile plot that gives local model quality of the protein.…”

Section: Model Generation and Validationmentioning

confidence: 99%

Targeting the ubiquitin-conjugating enzyme E2D4 for cancer drug discovery–a structure-based approach

et al. 2016

View full text Add to dashboard Cite

Cancer progression is a global burden. The incidence and mortality now reach 30 million deaths per year. Several pathways of cancer are under investigation for the discovery of effective therapeutics. The present study highlights the structural details of the ubiquitin protein 'Ubiquitin-conjugating enzyme E2D4' (UBE2D4) for the novel lead structure identification in cancer drug discovery process. The evaluation of 3D structure of UBE2D4 was carried out using homology modelling techniques. The optimized structure was validated by standard computational protocols. The active site region of the UBE2D4 was identified using computational tools like CASTp, Q-site Finder and SiteMap. The hydrophobic pocket which is responsible for binding with its natural receptor ubiquitin ligase CHIP (C-terminal of Hsp 70 interacting protein) was identified through proteinprotein docking study. Corroborating the results obtained from active site prediction tools and protein-protein docking study, the domain of UBE2D4 which is responsible for cancer cell progression is sorted out for further docking study. Virtual screening with large structural database like CB_Div Set and Asinex BioDesign small molecular structural database was carried out. The obtained new ligand molecules that have shown affinity towards UBE2D4 were considered for ADME prediction studies. The identified new ligand molecules with acceptable parameters of docking, ADME are considered as potent UBE2D4 enzyme inhibitors for cancer therapy.

show abstract

Knowledge-based potentials for proteins

Cited by 582 publications

References 52 publications

A desolvation barrier to hydrophobic cluster formation may contribute to the rate‐limiting step in protein folding

A desolvation barrier to hydrophobic cluster formation may contribute to the rate‐limiting step in protein folding

Enhanced sampling simulations to construct free-energy landscape of protein–partner substrate interaction

Targeting the ubiquitin-conjugating enzyme E2D4 for cancer drug discovery–a structure-based approach

Contact Info

Product

Resources

About