A Knowledge-Based Energy Function for Protein−Ligand, Protein−Protein, and Protein−DNA Complexes

Zhang, Chi; Liu, Song; Zhu, Qianqian; Zhou, Yaoqi

doi:10.1021/jm049314d

Cited by 275 publications

(287 citation statements)

References 104 publications

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“…The parameter, η, is an arbitrary constant that can be modified either to estimate freeenergy differences 27 or to tune the strength of the DFIRE energy term versus other energy terms. The histograms N obs in this work were obtained from analysis of a culled set of 1836 PDB structures from the PISCES server 38 which had better than 1.8-Å resolution and were less than 30% homologous to each other.…”

Section: Sponsoring/monitoring Agency Name(s) and Address(es) 10 Spomentioning

confidence: 99%

Assessment of Detection and Refinement Strategies for de novo Protein Structures Using Force Field and Statistical Potentials

Lee

Olson

2006

J. Chem. Theory Comput.

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Abstract:De novo predictions of protein structures at high resolution are plagued by the problem of detecting the native conformation from false energy minima. In this work, we provide an assessment of various detection and refinement protocols on a small subset of the secondgeneration all-atom Rosetta decoy set (Tsai et al. Proteins 2003, 53, 76-87) using two potentials: the all-atom CHARMM PARAM22 force field combined with generalized Born/surfacearea (GB-SA) implicit solvation and the DFIRE-AA statistical potential. Detection schemes included DFIRE-AA conformational scoring and energy minimization followed by scoring with both GB-SA and DFIRE-AA potentials. Refinement methods included short-time (1-ps) molecular dynamics simulations, temperature-based replica exchange molecular dynamics, and a new computational unfold/refold procedure. Refinement methods include temperature-based replica exchange molecular dynamics and a new computational unfold/refold procedure. Our results indicate that simple detection with only minimization is the best protocol for finding the most nativelike structures in the decoy set. The refinement techniques that we tested are generally unsuccessful in improving detection; however, they provide marginal improvements to some of the decoy structures. Future directions in the development of refinement techniques are discussed in the context of the limitations of the protocols evaluated in this study.

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Section: Sponsoring/monitoring Agency Name(s) and Address(es) 10 Spomentioning

confidence: 99%

Assessment of Detection and Refinement Strategies for de novo Protein Structures Using Force Field and Statistical Potentials

Lee

Olson

2006

J. Chem. Theory Comput.

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“…Scatter diagrams of these scores versus the experimentally determined IC 50 values for the test compounds showed that the measured IC 50 values most closely correlated with the G score (values listed in TABLE TWO). The G score is related to the binding free energy (G b ) by the empirically determined relationship ⌬G b ϭ (G score)/4 (reflecting the uniform weighting of the four Flex parameters in our analysis) (43,44). Apparent dissociation constants (K D ) for ligand transport interactions were then derived from the relationship K D ϭ exp(⌬G b /RT).…”

Section: M)mentioning

confidence: 99%

A Conserved Glutamate Residue in Transmembrane Helix 10 Influences Substrate Specificity of Rabbit OCT2 (SLC22A2)

Zhang

Shirahatti

Mahadevan

et al. 2005

Journal of Biological Chemistry

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OCT1 and OCT2 are involved in renal secretion of cationic drugs. Although they have similar selectivity for some substrates (e.g. tetraethylammonium (TEA)), they have distinct selectivities for others (e.g. cimetidine). We postulated that "homolog-specific residues," i.e. the 24 residues that are conserved in OCT1 orthologs as one amino acid and in OCT2 as a different one, influence homologspecific selectivity and examined the influence on substrate binding of three of these conserved residues that are found in the C-terminal half of the rabbit orthologs of OCT1/2. The N353L and R403I substitutions (OCT2 to OCT1) did not significantly change the properties of OCT2. However, the E447Q replacement shifted substrate selectivity toward an OCT1-like phenotype. Substitution of glutamate with cationic amino acids (E447K and E447R) abolished transport activity, and the E447L mutant displayed markedly reduced transport of TEA and cimetidine while retaining transport of 1-methyl-4-phenylpyridinium. In a novel homology model of the three-dimensional structure of OCT2, Glu 447 was found in a putative docking region within a hydrophilic cleft of the protein. Renal excretion is the principal pathway for elimination of many clinically used drugs and is the exclusive pathway for eliminating many end products of drug-metabolizing enzymes (1-3). Transporters in the renal tubule epithelium mediate secretion and thus play a critical role in detoxification (4). In addition, transporters control the exposure of renal cells to nephrotoxic drugs and environmental toxins and thereby influence xenobiotic-induced nephrotoxicity. A large fraction of these agents fall into the chemical class commonly referred to as "organic cations" (OCs), 2 i.e. a diverse array of primary, secondary, tertiary, or quaternary amines that have a net positive charge on the amine nitrogen at physiological pH. The proximal tubule is the primary site of renal OC secretion (3,5), and the first step in the process is OC entry from the blood into proximal cells across the peritubular (i.e. basolateral) membrane. Three homologous transporters (OCT1, OCT2, and OCT3) have been cloned and subsequently shown to be expressed in the basolateral membrane of proximal cells (1,6). In all species examined, including the human (7), the kinetic and selectivity profile of OCT3 and the comparatively low levels of mRNA and protein expression of this homolog in the kidney suggest that renal secretion is dominated by some combination of OCT1 and OCT2 activity. Perhaps the most convincing evidence of the significance of OCT1 and OCT2 in renal OC secretion is the observation that secretion of the prototypic OC, tetraethylammonium (TEA), is completely eliminated in OCT1/2 Ϫ/Ϫ mice (8).In human kidney, OCT2 appears to be the predominant OC transporter. Expression of mRNA for OCT2 far exceeds that for OCT1, and immunocytochemistry clearly shows a basolateral expression for OCT2 and little or no presence of OCT1 (9). There are, however, clear species differences in this profile, with subst...

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“…Nowadays there are several receptor based VS methods available, including AutoDock (Zhang et al, 2005), FlexX (Xing et al, 2004), Glide (Friesner & Banks, 2004), FlexScreen (Kokh & Wenzel, 2008), and ICM (Bursulaya et al, 2003), each of them having different technical features. Most modern methods use an atomistic representation of the protein and the ligand.…”

Section: Introductionmentioning

confidence: 99%

Recent Advances and Future Trend on the Emerging Role of GPUs as Platforms for Virtual Screening-Based Drug Discovery

Pérez‐Sánchez¹,

Cecilia²,

García³

2012

Virtual Screening

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A Knowledge-Based Energy Function for Protein−Ligand, Protein−Protein, and Protein−DNA Complexes

Cited by 275 publications

References 104 publications

Assessment of Detection and Refinement Strategies for de novo Protein Structures Using Force Field and Statistical Potentials

Assessment of Detection and Refinement Strategies for de novo Protein Structures Using Force Field and Statistical Potentials

A Conserved Glutamate Residue in Transmembrane Helix 10 Influences Substrate Specificity of Rabbit OCT2 (SLC22A2)

Recent Advances and Future Trend on the Emerging Role of GPUs as Platforms for Virtual Screening-Based Drug Discovery

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