Editing Molecular dynamics (section)

== Areas of application and limits ==

First used in [[theoretical physics]], the molecular dynamics method gained popularity in [[materials science]] soon afterward, and since the 1970s it has also been commonly used in [[biochemistry]] and [[biophysics]]. MD is frequently used to refine 3-dimensional structures of [[protein]]s and other [[macromolecule]]s based on experimental constraints from [[X-ray crystallography]] or [[Nuclear magnetic resonance spectroscopy|NMR spectroscopy]]. In physics, MD is used to examine the dynamics of atomic-level phenomena that cannot be observed directly, such as [[thin film]] growth and ion subplantation, and to examine the physical properties of [[nanotechnology|nanotechnological]] devices that have not or cannot yet be created. In biophysics and [[structural biology]], the method is frequently applied to study the motions of macromolecules such as proteins and [[nucleic acid]]s, which can be useful for interpreting the results of certain biophysical experiments and for modeling interactions with other molecules, as in [[ligand docking]]. In principle, MD can be used for [[De novo protein structure prediction|''ab initio'' prediction]] of [[protein structure]] by simulating [[protein folding|folding]] of the [[polypeptide chain]] from a [[random coil]]. MD can also be used to compute other thermodynamic properties such as drug solubilities and free energies of solvation <ref>{{Cite journal |last=Suarez |first=Adiran Garaizar |last2=Göller |first2=Andreas H. |last3=Beck |first3=Michael E. |last4=Gheta |first4=Sadra Kashef Ol |last5=Meier |first5=Katharina |date=2024-10-29 |title=Comparative assessment of physics-based in silico methods to calculate relative solubilities |url=https://link.springer.com/article/10.1007/s10822-024-00576-y |journal=Journal of Computer-Aided Molecular Design |language=en |volume=38 |issue=1 |pages=36 |doi=10.1007/s10822-024-00576-y |issn=1573-4951}}</ref>  including in polymers. <ref>{{Cite journal |last=Higginbotham |first=T. |last2=Meier |first2=K. |last3=Ramírez |first3=J. |last4=Garaizar |first4=A. |date=2025-02-03 |title=Predicting Drug-Polymer Compatibility in Amorphous Solid Dispersions by MD Simulation: On the Trap of Solvation Free Energies |url=https://pubs.acs.org/doi/10.1021/acs.molpharmaceut.4c00810 |journal=Molecular Pharmaceutics |volume=22 |issue=2 |pages=760–770 |doi=10.1021/acs.molpharmaceut.4c00810 |issn=1543-8384}}</ref>  

The results of MD simulations can be tested through comparison to experiments that measure molecular dynamics, of which a popular method is NMR spectroscopy. MD-derived structure predictions can be tested through community-wide experiments in Critical Assessment of Protein Structure Prediction ([[CASP]]), although the method has historically had limited success in this area. [[Michael Levitt (biophysicist)|Michael Levitt]], who shared the [[Nobel Prize]] partly for the application of MD to proteins, wrote in 1999 that CASP participants usually did not use the method due to "... a central embarrassment of [[molecular mechanics]], namely that [[energy minimization]] or molecular dynamics generally leads to a model that is less like the experimental structure".<ref name="Koehl">{{cite journal | vauthors = Koehl P, Levitt M | title = A brighter future for protein structure prediction | journal = Nature Structural Biology | volume = 6 | issue = 2 | pages = 108–111 | date = February 1999 | pmid = 10048917 | doi = 10.1038/5794 | author-link2 = Michael Levitt (biophysicist) | s2cid = 3162636 }}</ref> Improvements in computational resources permitting more and longer MD trajectories, combined with modern improvements in the quality of [[force field (chemistry)|force field]] parameters, have yielded some improvements in both structure prediction and [[homology model]] refinement, without reaching the point of practical utility in these areas; many identify force field parameters as a key area for further development.<ref>{{cite journal | vauthors = Raval A, Piana S, Eastwood MP, Dror RO, Shaw DE | title = Refinement of protein structure homology models via long, all-atom molecular dynamics simulations | journal = Proteins | volume = 80 | issue = 8 | pages = 2071–2079 | date = August 2012 | pmid = 22513870 | doi = 10.1002/prot.24098 | s2cid = 10613106 }}</ref><ref>{{cite journal | vauthors = Beauchamp KA, Lin YS, Das R, Pande VS | title = Are Protein Force Fields Getting Better? A Systematic Benchmark on 524 Diverse NMR Measurements | journal = Journal of Chemical Theory and Computation | volume = 8 | issue = 4 | pages = 1409–1414 | date = April 2012 | pmid = 22754404 | pmc = 3383641 | doi = 10.1021/ct2007814 }}</ref><ref>{{cite journal | vauthors = Piana S, Klepeis JL, Shaw DE | title = Assessing the accuracy of physical models used in protein-folding simulations: quantitative evidence from long molecular dynamics simulations | journal = Current Opinion in Structural Biology | volume = 24 | pages = 98–105 | date = February 2014 | pmid = 24463371 | doi = 10.1016/j.sbi.2013.12.006 | doi-access = free }}</ref>

MD simulation has been reported for [[pharmacophore]] development and [[drug design]].<ref name="pmid25751016">{{cite journal | vauthors = Choudhury C, Priyakumar UD, Sastry GN | title = Dynamics based pharmacophore models for screening potential inhibitors of mycobacterial cyclopropane synthase | journal = Journal of Chemical Information and Modeling | volume = 55 | issue = 4 | pages = 848–60 | date = April 2015 | pmid = 25751016 | doi = 10.1021/ci500737b }}</ref> For example, Pinto ''et al''. implemented MD simulations of [[Bcl-xL|Bcl-xL complexes]] to calculate average positions of critical [[Amino acid|amino acids]] involved in ligand binding.<ref name="pmid15143800">{{cite journal | vauthors = Pinto M, Perez JJ, Rubio-Martinez J | title = Molecular dynamics study of peptide segments of the BH3 domain of the proapoptotic proteins Bak, Bax, Bid and Hrk bound to the Bcl-xL and Bcl-2 proteins | journal = Journal of Computer-aided Molecular Design | volume = 18 | issue = 1 | pages = 13–22 | date = January 2004 | pmid = 15143800 | doi = 10.1023/b:jcam.0000022559.72848.1c | bibcode = 2004JCAMD..18...13P | s2cid = 11339000 }}</ref> Carlson ''et al''. implemented molecular dynamics simulations to identify compounds that complement a [[Receptor (biochemistry)|receptor]] while causing minimal disruption to the conformation and flexibility of the active site. Snapshots of the protein at constant time intervals during the simulation were overlaid to identify conserved binding regions (conserved in at least three out of eleven frames) for pharmacophore development. Spyrakis ''et al''. relied on a workflow of MD simulations, fingerprints for ligands and proteins (FLAP) and [[linear discriminant analysis]] (LDA) to identify the best ligand-protein conformations to act as pharmacophore templates based on retrospective [[Receiver operating characteristic|ROC]] analysis of the resulting pharmacophores. In an attempt to ameliorate structure-based drug discovery modeling, ''vis-à-vis'' the need for many modeled compounds, Hatmal ''et al''. proposed a combination of MD simulation and ligand-receptor intermolecular contacts analysis to discern critical intermolecular contacts (binding interactions) from redundant ones in a single ligand–protein complex. Critical contacts can then be converted into pharmacophore models that can be used for virtual screening.<ref name="pmid27722817">{{cite journal | vauthors = Hatmal MM, Jaber S, Taha MO | title = Combining molecular dynamics simulation and ligand-receptor contacts analysis as a new approach for pharmacophore modeling: beta-secretase 1 and check point kinase 1 as case studies | journal = Journal of Computer-aided Molecular Design | volume = 30 | issue = 12 | pages = 1149–1163 | date = December 2016 | pmid = 27722817 | doi = 10.1007/s10822-016-9984-2  | bibcode = 2016JCAMD..30.1149H | s2cid = 11561853 }}</ref>

An important factor is intramolecular [[hydrogen bond]]s,<ref name="Myers">{{cite journal | vauthors = Myers JK, Pace CN | title = Hydrogen bonding stabilizes globular proteins | journal = Biophysical Journal | volume = 71 | issue = 4 | pages = 2033–2039 | date = October 1996 | pmid = 8889177 | pmc = 1233669 | doi = 10.1016/s0006-3495(96)79401-8 | bibcode = 1996BpJ....71.2033M }}</ref> which are not explicitly included in modern force fields, but described as [[Coulomb interaction|Coulomb interactions]] of atomic [[Point charge|point charges]].{{Citation needed|date=February 2024|reason=Needs a citation to show this is a general issue and not an issue with specific forcefields}} This is a crude approximation because hydrogen bonds have a partially [[quantum mechanical]] and [[Quantum chemistry|chemical]] nature. Furthermore, electrostatic interactions are usually calculated using the [[Vacuum permittivity|dielectric constant of a vacuum]], even though the surrounding [[aqueous solution]] has a much higher dielectric constant. Thus, using the [[macroscopic]] dielectric constant at short interatomic distances is questionable. Finally, [[Van der Waals force|van der Waals interactions]] in MD are usually described by [[Lennard-Jones potential]]s<ref>{{Cite journal | vauthors = Lenhard J, Stephan S, Hasse H |date=June 2024 |title=On the History of the Lennard-Jones Potential |url=https://onlinelibrary.wiley.com/doi/10.1002/andp.202400115 |journal=Annalen der Physik |language=en |volume=536 |issue=6 |doi=10.1002/andp.202400115 |issn=0003-3804}}</ref><ref>{{Cite journal | vauthors = Fischer J, Wendland M |date=October 2023 |title=On the history of key empirical intermolecular potentials |journal=Fluid Phase Equilibria |language=en |volume=573 |pages=113876 |doi=10.1016/j.fluid.2023.113876|bibcode=2023FlPEq.57313876F |doi-access=free }}</ref> based on the [[Fritz London]] theory that is only applicable in a vacuum.{{Citation needed|date=February 2024|reason=needs a citation to show this true in the general case and not just specific forcefields.}} However, all types of van der Waals forces are ultimately of electrostatic origin and therefore depend on [[Permittivity|dielectric properties of the environment]].<ref name="Israelachvili">{{cite book | vauthors = Israelachvili J | author-link1 = Jacob Israelachvili | date = 1992 | title = Intermolecular and surface forces. | publisher = Academic Press | location = San Diego }}</ref> The direct measurement of attraction forces between different materials (as [[Hamaker constant]]) shows that "the interaction between [[Hydrocarbon|hydrocarbons]] across water is about 10% of that across vacuum".<ref name="Israelachvili" /> The environment-dependence of van der Waals forces is neglected in standard simulations, but can be included by developing polarizable force fields.