POVME 2.0: An Enhanced Tool for Determining Pocket Shape and Volume Characteristics

Durrant, Jacob D.; Votapka, Lane; Sørensen, Jesper Givskov; Amaro, Rommie E.

doi:10.1021/ct500381c

Cited by 206 publications

(218 citation statements)

References 84 publications

(153 reference statements)

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“…SHIFTXþ is an algorithm that takes into account only structural coordinates for chemical-shift prediction. The SHIFTX2 algorithm incorporates a number of sequence-based features from a training set as well as structural coordinates (44). Han et al (44) report that SHIFTX2 has improved correlation coefficients between observed and predicted backbone chemical shifts compared to the SHIFTXþ, so SHIFTX2 was used to predict chemical shifts where direct comparisons were made between MD simulation results and reported experimental values (see Fig.…”

Section: Shiftx2 and Shiftxd Calculationsmentioning

confidence: 99%

Capturing Invisible Motions in the Transition from Ground to Rare Excited States of T4 Lysozyme L99A

Schiffer

Feher

Malmstrom

et al. 2016

Biophysical Journal

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Proteins commonly sample a number of conformational states to carry out their biological function, often requiring transitions from the ground state to higher-energy states. Characterizing the mechanisms that guide these transitions at the atomic level promises to impact our understanding of functional protein dynamics and energy landscapes. The leucine-99-toalanine (L99A) mutant of T4 lysozyme is a model system that has an experimentally well characterized excited sparsely populated state as well as a ground state. Despite the exhaustive study of L99A protein dynamics, the conformational changes that permit transitioning to the experimentally detected excited state (~3%, DG~2 kcal/mol) remain unclear. Here, we describe the transitions from the ground state to this sparsely populated excited state of L99A as observed through a single molecular dynamics (MD) trajectory on the Anton supercomputer. Aside from detailing the ground-to-excited-state transition, the trajectory samples multiple metastates and an intermediate state en route to the excited state. Dynamic motions between these states enable cavity surface openings large enough to admit benzene on timescales congruent with known rates for benzene binding. Thus, these fluctuations between rare protein states provide an atomic description of the concerted motions that illuminate potential path(s) for ligand binding. These results reveal, to our knowledge, a new level of complexity in the dynamics of buried cavities and their role in creating mobile defects that affect protein dynamics and ligand binding.

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Section: Shiftx2 and Shiftxd Calculationsmentioning

confidence: 99%

Capturing Invisible Motions in the Transition from Ground to Rare Excited States of T4 Lysozyme L99A

Schiffer

Feher

Malmstrom

et al. 2016

Biophysical Journal

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“…To monitor the sugar pucker of target nucleotide, we used cpptraj. [69][70][71] Pocket volumes were studied using POVME3.0 [72][73][74] and visualized using Visual Molecular Dynamics. 75 The pocket region was defined by a set of inclusion spheres which cover the observed DNA binding region ( Figure S1).…”

Section: Methodsmentioning

confidence: 99%

Determinants of Substrate Specificity in APOBEC3B

Wagner

Demir²,

Carpenter³

et al. 2018

Preprint

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APOBEC3B (A3B) is a newly discovered driver of mutation in many cancers. We use computational tools to revert a recent crystal structure of an A3B construct to its native sequence, and run molecular dynamics simulations to study its underlying dynamics and substrate recognition mechanisms. The A3B oligonucleotide substrate simulations show a series of dynamic substrate protein contacts that correlate with previous work on A3B substrate selectivity. A second series of simulations in which the target cytosine nucleotide was computationally mutated from a deoxyribose to a ribose showed a change in sugar ring pucker, leading to a rearrangement of the binding site and revealing a potential intermediate in the binding pathway. Finally, apo simulations of A3B beginning in the open state experience a rapid and consistent closure of the binding site, reaching a conformation incompatible with substrate binding. These simulations agree with previous experimental studies, and we report the atomistic details of these events to further therapeutic studies on A3B. IntroductionThe APOBEC3 (A3) family of cytidine deaminases is a recently discovered endogenous source of mutation in cancer. 1,2 Previously, A3 proteins were studied in the context of their interactions with viruses and efforts were undertaken to discover small molecules that modulate the mutational activities of the virally restrictive APOBEC3G enzyme. 3,4 Recent studies have linked cancer progression and recurrence to A3 activity. 5-9 A3 proteins have specific substrate sequence preferences, and analyses of some cancer genomes have shown an enrichment of A3 mutation signatures. [10][11][12][13][14][15] Recent evidence suggests that APOBEC3B (A3B) is an important driver of tumor progression in the A3 family. 16,17

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“…WebChemViewer [91] is an online viewer for viewing and interacting with lists of compounds and their associated data.…”

Section: Qsar/admet Modelingmentioning

confidence: 99%

“…POVME (POcket Volume MEasurer) [91] is a tool for measuring and characterizing pocket volumes that includes a graphical user interface.…”

Section: Virtual Screening and Ligand Designmentioning

confidence: 99%

Open source molecular modeling

Pirhadi

Sunseri

2016

Journal of Molecular Graphics and Modelling

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The success of molecular modeling and computational chemistry efforts are, by definition, dependent on quality software applications. Open source software development provides many advantages to users of modeling applications, not the least of which is that the software is free and completely extendable. In this review we categorize, enumerate, and describe available open source software packages for molecular modeling and computational chemistry.

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POVME 2.0: An Enhanced Tool for Determining Pocket Shape and Volume Characteristics

Cited by 206 publications

References 84 publications

Capturing Invisible Motions in the Transition from Ground to Rare Excited States of T4 Lysozyme L99A

Capturing Invisible Motions in the Transition from Ground to Rare Excited States of T4 Lysozyme L99A

Determinants of Substrate Specificity in APOBEC3B

Open source molecular modeling

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