scholarly journals Z-DNA as a Touchstone for Additive Empirical Force Fields and a Refinement of the Alpha/Gamma DNA torsions for AMBER

2021 ◽  
Author(s):  
Marie Zgarbova ◽  
Jiri Sponer ◽  
Petr Jurecka
Keyword(s):  
Force Fields ◽  
Difficult Case ◽  
Additive Effects ◽  
Correct Description ◽  
Dna Complexes ◽  
Dna Motifs ◽  
Z Dna ◽  
Living Organisms ◽  
The Stability ◽  
Amber Force Fields

Although current AMBER force fields are relatively accurate for canonical B-DNA, many non-canonical structures are still described incorrectly. As non-canonical motifs are attracting increasing attention due to the role they play in living organisms, further improvement is desirable. Here, we have chosen Z-DNA molecule, can be considered a touchstone of the universality of empirical force fields, since the non-canonical α and γ backbone conformations native to Z-DNA are also found in protein-DNA complexes, i-motif DNA and other non-canonical DNAs. We show that spurious α/γ conformations occurring in simulations with current AMBER force fields, OL15 and bsc1, are largely due to inaccurate α/γ parameterization. Moreover, stabilization of native Z-DNA substates involving γ = trans conformations appears to be in conflict with the correct description of the canonical B-DNA structure. Because the balance of the native and spurious conformations is influenced by non-additive effects, this is a difficult case for an additive dihedral energy scheme such as AMBER. We propose new α/γ parameters, denoted OL21, and show that they improve the stability of native α/γ Z-DNA substates while keeping the canonical DNA description virtually unchanged, and thus represent a reasonable compromise within the additive force field framework. Although further extensive testing is needed, the new modification appears to be a promising step towards a more reliable description of non-canonical DNA motifs and provides the best performance for Z-DNA molecules among current AMBER force fields.

scholarly journals Continuous B- to A- Transition in Protein-DNA Binding - How Well Is It Described by Current AMBER Force Fields?

2022 ◽  
Author(s):  
Petr Jurecka ◽  
Marie Zgarbova ◽  
Filip Cerny ◽  
Jan Salomon
Keyword(s):  
Force Fields ◽  
Md Simulations ◽  
Binding Motif ◽  
Dna Complexes ◽  
Continuous Transition ◽  
Correct Sequence ◽  
Protein Dna Interactions ◽  
Intermediate States ◽  
Amber Force Fields ◽  
Dna Complex

When DNA interacts with a protein, its structure often undergoes significant conformational adaptation. Perhaps the most common is the transition from canonical B-DNA towards the A-DNA form, which is not a two-state, but rather a continuous transition. The A- and B- forms differ mainly in sugar pucker P (north/south) and glycosidic torsion χ (high-anti/anti). The combination of A-like P and B-like χ (and vice versa) represents the nature of the intermediate states lying between the pure A- and B- forms. In this work, we study how the A/B equilibrium and in particular the A/B intermediate states, which are known to be over-represented at protein-DNA interfaces, are modeled by current AMBER force fields. Eight protein-DNA complexes and their naked (unbound) DNAs were simulated with OL15 and bsc1 force fields as well as an experimental combination OL15χOL3. We found that while the geometries of the A-like intermediate states in the molecular dynamics (MD) simulations agree well with the native X-ray geometries found in the protein-DNA complexes, their populations (stabilities) are significantly underestimated. Different force fields predict different propensities for A-like states growing in the order OL15 < bsc1 < OL15χOL3, but the overall populations of the A-like form are too low in all of them. Interestingly, the force fields seem to predict the correct sequence-dependent A-form propensity, as they predict larger populations of the A-like form in naked (unbound) DNA in those steps that acquire A-like conformations in protein-DNA complexes. The instability of A-like geometries in current force fields may significantly alter the geometry of the simulated protein-DNA complex, destabilize the binding motif, and reduce the binding energy, suggesting that refinement is needed to improve description of protein-DNA interactions in AMBER force fields.

Assessment of AMBER Force Fields for Simulations of ssDNA

2021 ◽  
Vol 17 (2) ◽  
pp. 1208-1217
Author(s):  
Thomas J. Oweida ◽  
Ho Shin Kim ◽  
Johnny M. Donald ◽  
Abhishek Singh ◽  
Yaroslava G. Yingling
Keyword(s):  
Force Fields ◽  
Amber Force Fields

scholarly journals BALLAST WATER POLLUTION RISK ASSESSMENT IN THE BLACK SEA

2021 ◽  
Vol 10 (4) ◽  
pp. 35-40
Author(s):  
Vasile RAŢᾸ ◽  
Liliana RUSU
Keyword(s):  
Risk Assessment ◽  
Black Sea ◽  
Marine Environment ◽  
Ballast Water ◽  
Safety Net ◽  
The Black Sea ◽  
Natural Food ◽  
Economic Activities ◽  
Living Organisms ◽  
The Stability

Since the emergence of humanity, the marine environment has provided a safety net in many ways, has fostered socio-economic development, creating links between states, between continents. In the same time, it represents a priority source of food for a considerable percentage of the population. The same marine environment also creates solutions to current global problems, as a potential source of sustainable energy for the future. In recent decades, the stability of this ecosystem has been  considerably shaken by the various types of pollution resulting from human activities. The Black Sea is not immune to these results from economic activities, such as the transport of goods by water, which creates the context for the migration of living organisms from one geographical region to another. The threat of ecosystems has been intensified by the process of globalization, by changing the natural food chains following the accidental introduction of non- indigenous marine life by discharging ballast water from ship tanks. Risk assessment to limit the effects of this biohazard problem is the first step in a normal regional chain of action..

Thermodynamics of Helix formation in small peptides of varying lengthin vacuo, implicit solvent and explicit solvent: Comparison between AMBER force fields

2019 ◽  
Vol 18 (03) ◽  
pp. 1950015
Author(s):  
Zhaoxi Sun ◽  
Xiaohui Wang
Keyword(s):  
Amino Acids ◽  
Free Energy ◽  
Hydrogen Bonds ◽  
Force Fields ◽  
Implicit Solvent ◽  
Conformational Ensemble ◽  
Helix Formation ◽  
Solvent Models ◽  
Explicit Solvent ◽  
Amber Force Fields

Helix formation is of great significance in protein folding. The helix-forming tendencies of amino acids are accumulated along the sequence to determine the helix-forming tendency of peptides. Computer simulation can be used to model this process in atomic details and give structural insights. In the current work, we employ equilibrate-state free energy simulation to systematically study the folding/unfolding thermodynamics of a series of mutated peptides. Two AMBER force fields including AMBER99SB and AMBER14SB are compared. The new 14SB force field uses refitted torsion parameters compared with 99SB and they share the same atomic charge scheme. We find that in vacuo the helix formation is mutation dependent, which reflects the different helix propensities of different amino acids. In general, there are helix formers, helix indifferent groups and helix breakers. The helical structure becomes more favored when the length of the sequence becomes longer, which arises from the formation of additional backbone hydrogen bonds in the lengthened sequence. Therefore, the helix indifferent groups and helix breakers will become helix formers in long sequences. Also, protonation-dependent helix formation is observed for ionizable groups. In 14SB, the helical structures are more stable than in 99SB and differences can be observed in their grouping schemes, especially in the helix indifferent group. In solvents, all mutations are helix indifferent due to protein–solvent interactions. The decrease in the number of backbone hydrogen bonds is the same with the increase in the number of protein–water hydrogen bonds. The 14SB in explicit solvent is able to capture the free energy minima in the helical state while 14SB in implicit solvent, 99SB in explicit solvent and 99SB in implicit solvent cannot. The helix propensities calculated under 14SB agree with the corresponding experimental values, while the 99SB results obviously deviate from the references. Hence, implicit solvent models are unable to correctly describe the thermodynamics even for the simple helix formation in isolated peptides. Well-developed force fields and explicit solvents are needed to correctly describe the protein dynamics. Aside from the free energy, differences in conformational ensemble under different force fields in different solvent models are observed. The numbers of hydrogen bonds formed under different force fields agree and they are mostly determined by the solvent model.

scholarly journals An ATP/ADP-Dependent Molecular Switch Regulates the Stability of p53-DNA Complexes

1999 ◽  
Vol 19 (11) ◽  
pp. 7501-7510 ◽  
Author(s):  
Andrei L. Okorokov ◽  
Jo Milner
Keyword(s):  
Dna Damage ◽  
Dna Binding ◽  
Cellular Response ◽  
Atp Hydrolysis ◽  
P53 Protein ◽  
Molecular Switch ◽  
Dna Complexes ◽  
Switch Mechanism ◽  
The Stability ◽  
First Time

ABSTRACT Interaction with DNA is essential for the tumor suppressor functions of p53. We now show, for the first time, that the interaction of p53 with DNA can be stabilized by small molecules, such as ADP and dADP. Our results also indicate an ATP/ADP molecular switch mechanism which determines the off-on states for p53-DNA binding. This ATP/ADP molecular switch requires dimer-dimer interaction of the p53 tetramer. Dissociation of p53-DNA complexes by ATP is independent of ATP hydrolysis. Low-level ATPase activity is nonetheless associated with ATP-p53 interaction and may serve to regenerate ADP-p53, thus recycling the high-affinity DNA binding form of p53. The ATP/ADP regulatory mechanism applies to two distinct types of p53 interaction with DNA, namely, sequence-specific DNA binding (via the core domain of the p53 protein) and binding to sites of DNA damage (via the C-terminal domain). Further studies indicate that ADP not only stabilizes p53-DNA complexes but also renders the complexes susceptible to dissociation by specific p53 binding proteins. We propose a model in which the DNA binding functions of p53 are regulated by an ATP/ADP molecular switch, and we suggest that this mechanism may function during the cellular response to DNA damage.

scholarly journals Meaningful measurements of maneuvers: People with incomplete spinal cord injury ‘step up’ to the challenges of altered stability requirements

2021 ◽  
Vol 18 (1) ◽  
Author(s):  
Wendy L. Ochs ◽  
Jane Woodward ◽  
Tara Cornwell ◽  
Keith E. Gordon
Keyword(s):  
Spinal Cord ◽  
Spinal Cord Injury ◽  
Force Field ◽  
Force Fields ◽  
Center Of Mass ◽  
Lateral Force ◽  
Step Width ◽  
Incomplete Spinal Cord Injury ◽  
Cord Injury ◽  
The Stability

Abstract Background Many people with incomplete spinal cord injury (iSCI) have the ability to maneuver while walking. However, neuromuscular impairments create challenges to maintain stability. How people with iSCI maintain stability during walking maneuvers is poorly understood. Thus, this study compares maneuver performance in varying external conditions between persons with and without iSCI to better understand maneuver stabilization strategies in people with iSCI. Methods Participants with and without iSCI walked on a wide treadmill and were prompted to perform lateral maneuvers between bouts of straight walking. Lateral force fields applied to the participants’ center of mass amplified or attenuated the participants’ movements, thereby increasing the capability of the study to capture behavior at varied levels of challenge to stability. Results By examining metrics of stability, step width, and center of mass dynamics, distinct strategies emerged following iSCI. The minimum margin of stability (MOSmin) on each step during maneuvers indicated persons with iSCI generally adapted to amplified and attenuated force fields with increased stability compared to persons without iSCI, particularly using increased step width and reduced center of mass excursion on maneuver initiation. In the amplified field, however, persons with iSCI had a reduced MOSmin when terminating a maneuver, likely due to the challenge of the force field opposing the necessary lateral braking. Persons without iSCI were more likely to rely on or oppose the force field when appropriate for movement execution. Compared to persons with iSCI, they reduced their MOSmin to initiate maneuvers in the attenuated and amplified fields and increased their MOSmin to arrest maneuvers in the amplified field. Conclusions The different force fields were successful in identifying relatively subtle strategy differences between persons with and without iSCI. Specifically, persons with iSCI adopted increased step width and reduction in center of mass excursion to increase maneuver stability in the amplified field. The amplified field may provoke practice of stable and efficient initiation and arrest of walking maneuvers. Overall, this work allows better framing of the stability mechanisms used following iSCI to perform walking maneuvers.

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