scholarly journals Simulating Multiple Substrate-Binding Events by γ-Glutamyltransferase Using Accelerated Molecular Dynamics

2020 ◽  
Vol 124 (45) ◽  
pp. 10104-10116
Author(s):  
Francesco Oliva ◽  
Jose C. Flores-Canales ◽  
Stefano Pieraccini ◽  
Carlo F. Morelli ◽  
Maurizio Sironi ◽  
...  
Keyword(s):  
Molecular Dynamics ◽  
Substrate Binding ◽  
Accelerated Molecular Dynamics ◽  
Multiple Substrate

scholarly journals Simulating Multiple Substrate Binding Events by γ-Glutamyltransferase using Accelerated Molecular Dynamics

2020 ◽  
Author(s):  
Francesco Oliva ◽  
Jose C. Flores-Canales ◽  
Stefano Pieraccini ◽  
Carlo F. Morelli ◽  
Maurizio Sironi ◽  
...  
Keyword(s):  
Molecular Dynamics ◽  
Electrostatic Interactions ◽  
Substrate Binding ◽  
Conformational Dynamics ◽  
Binding Pocket ◽  
Thermal Fluctuations ◽  
Accelerated Molecular Dynamics ◽  
Binding Cavity ◽  
Multiple Substrate ◽  
Open States

Abstractγ-glutamyltransferase (GGT) is an enzyme that uses γ-glutamyl compounds as substrate and catalyzes their transfer into a water molecule or an acceptor substrate with varied physiological-function in bacteria, plants and animals. Crystal structures of GGT are known for different species and in different states of the chemical reaction; however, structural dynamics of the substrate binding to the catalytic site of GGT is unknown. Here, we modeled Escherichia Coli GGT’s glutamine binding by using a swarm of accelerated molecular dynamics (aMD) simulations. Characterization of multiple binding events identified three structural binding motifs composed of polar residues in the binding pocket that govern glutamine binding into the active site. Simulated open and closed conformations of a lid-loop protecting the binding cavity suggests its role as a gating element by allowing or blocking substrates entry into the binding pocket. Partially open states of the lid-loop are accessible within thermal fluctuations, while the estimated free energy cost of a complete open state is 2.4 kcal/mol. Our results suggest that both specific electrostatic interactions and GGT conformational dynamics dictate the molecular recognition of substrate-GGT complexes.

scholarly journals Anti-TNF Alpha Antibody Humira with pH-dependent Binding Characteristics: A constant-pH Molecular Dynamics, Gaussian Accelerated Molecular Dynamics, and In Vitro Study

Biomolecules ◽  
2021 ◽  
Vol 11 (2) ◽  
pp. 334
Author(s):  
Shih-Ting Hong ◽  
Yu-Cheng Su ◽  
Yu-Jen Wang ◽  
Tian-Lu Cheng ◽  
Yeng-Tseng Wang
Keyword(s):  
Molecular Dynamics ◽  
Tnf Alpha ◽  
Complex Structures ◽  
Binding Characteristics ◽  
Accelerated Molecular Dynamics ◽  
Constant Ph ◽  
Ph Dependent ◽  
Constant Ph Molecular Dynamics ◽  
Antibody Drug

Humira is a monoclonal antibody that binds to TNF alpha, inactivates TNF alpha receptors, and inhibits inflammation. Neonatal Fc receptors can mediate the transcytosis of Humira–TNF alpha complex structures and process them toward degradation pathways, which reduces the therapeutic effect of Humira. Allowing the Humira–TNF alpha complex structures to dissociate to Humira and soluble TNF alpha in the early endosome to enable Humira recycling is crucial. We used the cytoplasmic pH (7.4), the early endosomal pH (6.0), and pKa of histidine side chains (6.0–6.4) to mutate the residues of complementarity-determining regions with histidine. Our engineered Humira (W1-Humira) can bind to TNF alpha in plasma at neutral pH and dissociate from the TNF alpha in the endosome at acidic pH. We used the constant-pH molecular dynamics, Gaussian accelerated molecular dynamics, two-dimensional potential mean force profiles, and in vitro methods to investigate the characteristics of W1-Humira. Our results revealed that the proposed Humira can bind TNF alpha with pH-dependent affinity in vitro. The W1-Humira was weaker than wild-type Humira at neutral pH in vitro, and our prediction results were close to the in vitro results. Furthermore, our approach displayed a high accuracy in antibody pH-dependent binding characteristics prediction, which may facilitate antibody drug design. Advancements in computational methods and computing power may further aid in addressing the challenges in antibody drug design.

GPU-accelerated molecular dynamics: State-of-art software performance and porting from Nvidia CUDA to AMD HIP

2021 ◽  
pp. 109434202110082
Author(s):  
Nikolay Kondratyuk ◽  
Vsevolod Nikolskiy ◽  
Daniil Pavlov ◽  
Vladimir Stegailov
Keyword(s):  
Molecular Dynamics ◽  
High Performance ◽  
Software Performance ◽  
Computing Systems ◽  
Accelerated Molecular Dynamics ◽  
Nvidia Cuda ◽  
Software And Hardware ◽  
Management Capabilities ◽  
Utilization Time ◽  
Performance Computing

Classical molecular dynamics (MD) calculations represent a significant part of the utilization time of high-performance computing systems. As usual, the efficiency of such calculations is based on an interplay of software and hardware that are nowadays moving to hybrid GPU-based technologies. Several well-developed open-source MD codes focused on GPUs differ both in their data management capabilities and in performance. In this work, we analyze the performance of LAMMPS, GROMACS and OpenMM MD packages with different GPU backends on Nvidia Volta and AMD Vega20 GPUs. We consider the efficiency of solving two identical MD models (generic for material science and biomolecular studies) using different software and hardware combinations. We describe our experience in porting the CUDA backend of LAMMPS to ROCm HIP that shows considerable benefits for AMD GPUs comparatively to the OpenCL backend.

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