Protein thermal stability: insights from atomic displacement parameters (B values)

Parthasarathy, S.; Murthy, M.R.N.

doi:10.1093/protein/13.1.9

Cited by 175 publications

(117 citation statements)

References 29 publications

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“…The Debye-Waller temperature factors (also called B -factors) obtained from X -ray data provide experimental measures of this sort of flexibility. 100,101 In addition, molecular dynamics was invented for the study of this type of motion. 101a Indeed, almost countless numbers of papers have been published that use molecular dynamics simulations to explore local flexibility.…”

Section: Random Coilmentioning

confidence: 99%

Intrinsically disordered protein

Dunker

Lawson

Brown

et al. 2001

Journal of Molecular Graphics and Modelling

2,101

2,085

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Proteins can exist in a trinity of structures: the ordered state, the molten globule and the random coil. Five examples follow which suggest that native protein structure can correspond to any of the three states (not just the ordered state) and that protein function can arise from any of the three states and their transitions. 1. In a process that likely mimics infection, fd phage converts from the ordered into the disordered molten globular state. 2. Nucleosome hyperacetylation is crucial to DNA replication and transcription; this chemical modification greatly increases the net negative charge of the nucleosome core particle. We propose that the increased charge imbalance promotes its conversion to a much less rigid form. 3. Clusterin contains an ordered domain and also a native molten globular region. The molten globular domain likely functions as a proteinaceous detergent for cell remodeling and removal of apoptotic debris. 4. In a critical signaling event, a helix in calcineurin becomes bound and surrounded by calmodulin, thereby turning on calcineurin's serine/threonine phosphatase activity.Locating the calcineurin helix within a region of disorder is essential for enabling calmodulin to surround its target upon binding. 5. Calsequestrin regulates calcium levels in the sarcoplasmic reticulum by binding about 50 ions/molecule. Disordered polyanion tails at the carboxy terminus bind many of these calcium ions, perhaps without adopting a unique structure. In addition to these examples, 16 more proteins with native disorder will be discussed. These disordered regions include molecular recognition domains, protein folding inhibitors, flexible linkers, entropic springs, entropic clocks and entropic bristles.Motivated by such examples of intrinsic disorder, we are studying the relationships between amino acid sequence and order/disorder, and from this information we are predicting intrinsic order/disorder from amino acid sequence.The sequence/structure relationships indicate that disorder is an encoded property, and the predictions strongly suggest that proteins in nature are much richer in intrinsic disorder than are those in the Protein Data Bank. Recent predictions on 29 genomes indicate that proteins from eucaryotes apparently have more intrinsic disorder than those from either bacteria or archaea, with typically > 30 % of eucaryotic proteins having disordered regions of length = 50 consecutive residues.

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Section: Random Coilmentioning

confidence: 99%

Intrinsically disordered protein

Dunker

Lawson

Brown

et al. 2001

Journal of Molecular Graphics and Modelling

2,101

2,085

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“…B-factor investigation gives comprehension of stability, dynamics, and flexibility of amino acids [17]. Protein flexibility assumes a critical part in protein flexibility and designing of the drug molecules [18]. There are different sorts of contacts which require flexibility of certain amino acids.…”

Section: Identification Of Binding Site Residues Of Ros1mentioning

confidence: 99%

Structural and Functional Impact of G2032r Mutation in Ros1 – A Theoretical Perspective

Kumar

Shanthi

Ramanathan

2017

Asian J Pharm Clin Res

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Objective: Drug resistance is an imperative issue in the treatment of patients with lung cancer. In this work, investigation of the drug resistance mechanism of G2032R mutation in ROS1 is carried out using computational simulation techniques.Methods: Molecular docking and molecular dynamics (MD) simulation approach have been utilized to uncover the mechanism behind crizotinib resistance in ROS1 at a molecular level. Normal mode analysis was carried out using ElNemo server which examines the movements and conformational changes in the protein structure. ArgusLab, PEARLS, and Autodock were employed for the docking analysis, whereas GROMACS package 4.5.3 was used for MD simulation approach. Results:The results from our analysis indicates that wild-type ROS1 (Protein Data Bank Code 3ZBF) could be more crucial for the crizotinib binding as it indicates largest binding affinity, minimum number of H-bonds, and higher flexibility than mutant-type ROS1. Moreover, the theoretical basis for the cause of drug insensitivity is the differences in the electrostatic properties of binding site residues between the wild and mutant ROS1 structures. Our analysis theoretically suggests that E-2027 is a key residue responsible for the ROS1 drug selectivity.Conclusion: Molecular docking and MD simulation results provide an explanation of the resistance caused by G2032R and may give a key clue for the drug design to encounter drug resistance.

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“…These can be related to the normalized mean square displacements (<R 2 >) (Ringe & Petsko 1986;Yuan et al 2005). Therefore, <R2> analysis is likely to provide newer insights into protein dynamics, flexibility of amino acids, and protein stability (Parthasarathy & Murthy et al 2000). It is worth mentioning that protein flexibility is important for protein function, rational drug design, and maintaining various types of interactions (Carlson & McCammon 2000).…”

Section: Data Setmentioning

confidence: 99%

Analysis of hepatitis B virus drug-resistant mutation (M204V) using molecular dynamics simulation techniques

Muralidharan

Ramanathan

2014

Biologia

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Hepatitis B virus (HBV) is the most common cause of liver infection. This can be treated by targeting HBV DNA polymerase (HDP). Although many drugs are available for the treatment, lamivudine is widely used because of its good safety profiles. Lamivudine targets the reverse transcriptase activity of HDP and restricts the viral growth. However, the available literature evidence showed that the mutations in the catalytic site of tyrosine (Y203), methionine (M204), aspartic acid (D205) and aspartic acid (D206) will significantly reduce the efficacy of lamivudine and creates a resistance. In particular, M204V mutation affects the drug binding mechanism and cause resistance to lamivudine. Therefore, in the present study, we made an attempt to understand the mechanism of lamivudine resistance with the aid of computational techniques. The docking results suggest that lamivudine was found to adopt most promising conformations with native type HDP by identifying M204 as a prospective partner for making polar contacts as compared to the mutant type HDP. The molecular dynamic (MD) results showed that the average atom, especially atoms of the native-type HDP-lamivudine complex, movements were small, displayed fast convergence of energy and charges in geometry. This highlights the stable binding of the lamivudine with native-type HDP as compared to mutant type HDP. The normalized mean square displacement and root mean square fluctuation analysis certainly indicates conformational changes in the HDP structure due to M204V mutation. Furthermore, the hydrogen bond analysis from the MD study demonstrated that there is decreased number of intermolecular hydrogen bonds in mutant HDP-lamivudine complex than that in the native-type HDP-lamivudine complex.

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Protein thermal stability: insights from atomic displacement parameters (B values)

Cited by 175 publications

References 29 publications

Intrinsically disordered protein

Intrinsically disordered protein

Structural and Functional Impact of G2032r Mutation in Ros1 – A Theoretical Perspective

Analysis of hepatitis B virus drug-resistant mutation (M204V) using molecular dynamics simulation techniques

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