We review a selection of methods for performing enhanced sampling in molecular dynamics simulations. We consider methods based on collective variable biasing and on tempering, and offer both historical and contemporary perspectives. In collective-variable biasing, we first discuss methods stemming from thermodynamic integration that use mean force biasing, including the adaptive biasing force algorithm and temperature acceleration. We then turn to methods that use bias potentials, including umbrella sampling and metadynamics. We next consider parallel tempering and replica-exchange methods. We conclude with a brief presentation of some combination methods.

We show how to apply the method of temperature-accelerated molecular dynamics (TAMD) in collective variables [Maragliano L, Vanden-Eijnden E (2006) Chem Phys Lett 426:168–175] to sample the conformational space of multidomain proteins in all-atom, explicitly solvated molecular dynamics simulations. The method allows the system to hyperthermally explore the free-energy surface in a set of collective variables computed at the physical temperature. As collective variables, we pick Cartesian coordinates of centers of contiguous subdomains. The method is applied to the GroEL subunit, a 55-kDa, three-domain protein, and HIV-1 gp120. For GroEL, the method induces in about 40 ns conformational changes that recapitulate the t → r ^′′ transition and are not observed in unaccelerated molecular dynamics: The apical domain is displaced by 30 Å, with a twist of 90° relative to the equatorial domain, and the root-mean-squared deviation relative to the r ^′′ conformer is reduced from 13 to 5 Å, representing fairly high predictive capability. For gp120, the method predicts both counterrotation of inner and outer domains and disruption of the so-called bridging sheet. In particular, TAMD on gp120 initially in the CD4-bound conformation visits conformations that deviate by 3.6 Å from the gp120 conformer in complex with antibody F105, again reflecting good predictive capability. TAMD generates plausible all-atom models of the so-far structurally uncharacterized unliganded conformation of HIV-1 gp120, which may prove useful in the development of inhibitors and immunogens. The fictitious temperature employed also gives a rough estimate of 10 kcal/mol for the free-energy barrier between conformers in both cases.

The entry of HIV-1 into target cells is mediated by the viral envelope glycoproteins (Env). Binding to the CD4 receptor triggers a cascade of conformational changes in distant domains that move Env from a functionally “closed” State 1 to more “open” conformations, but the molecular mechanisms underlying allosteric regulation of these transitions are still elusive. Here, we develop chemical probes that block CD4-induced conformational changes in Env and use them to identify a potential control switch for Env structural rearrangements. We identify the gp120 β20–β21 element as a major regulator of Env transitions. Several amino acid changes in the β20–β21 base lead to open Env conformations, recapitulating the structural changes induced by CD4 binding. These HIV-1 mutants require less CD4 to infect cells and are relatively resistant to State 1-preferring broadly neutralizing antibodies. These data provide insights into the molecular mechanism and vulnerability of HIV-1 entry.

The seasonal nature of outbreaks of respiratory viral infections with increased transmission during low temperatures has been well established. Accordingly, temperature has been suggested to play a role on the viability and transmissibility of SARS-CoV-2, the virus responsible for the COVID-19 pandemic. The receptor-binding domain (RBD) of the Spike glycoprotein is known to bind to its host receptor angiotensin-converting enzyme 2 (ACE2) to initiate viral fusion. Using biochemical, biophysical, and functional assays to dissect the effect of temperature on the receptor–Spike interaction, we observed a significant and stepwise increase in RBD-ACE2 affinity at low temperatures, resulting in slower dissociation kinetics. This translated into enhanced interaction of the full Spike glycoprotein with the ACE2 receptor and higher viral attachment at low temperatures. Interestingly, the RBD N501Y mutation, present in emerging variants of concern (VOCs) that are fueling the pandemic worldwide (including the B.1.1.7 (α) lineage), bypassed this requirement. This data suggests that the acquisition of N501Y reflects an adaptation to warmer climates, a hypothesis that remains to be tested.

We present a dual-resolution coarse-graining scheme for efficient molecular dynamics simulations of bisphenol-$A$-polycarbonate $(\mathrm{BP}-A-\mathrm{PC})$ liquids in contact with a (111) nickel surface. The essential feature of this model is the strong adsorption of phenoxy chain ends, and the absence of adsorption by other parts of the chains. Details of how phenoxy chain ends interact with the nickel surface were extracted from Car-Parrinello molecular dynamics calculations of adsorption of phenol on nickel. These calculations show that phenol adsorption on nickel is short ranged $(<\mathrm{}3\mathrm{}\mathrm{\AA })$ and strongly dependent on the ${\mathrm{C}}_1-{\mathrm{C}}_4$ orientation of the ring. The structure of $\mathrm{BP}-A-\mathrm{PC}$ prevents internal phenylene groups from interacting with the surface, due to steric hindrances from the noninteracting isopropylidenes. These dependencies are incorporated in the coarse-grained model of the $\mathrm{BP}-A-\mathrm{PC}$ chain by resolving chain-terminating carbonate groups with atomistic detail, while the rest of the chain is represented by coarsened “beads.” This allows specification of the ${\mathrm{C}}_1-{\mathrm{C}}_4$ orientation of the terminal phenoxy groups, while overall allowing for system equilibration with reasonable computer time. We simulate liquids of up to 240 chains of ten chemical repeat units, confined in a slit pore formed by two frozen (111) planes of atoms with the lattice spacing of nickel. We find that the strong adsorption of chain ends has a large effect on the liquid structure through a distance of more than two bulk radii of gyration from the surface. These effects are explained by a competition among single- and double-end adsorption, and dense packing. The structure of the interface less than $10\mathrm{\AA }$ from the wall is greatly sensitive to the orientational dependence of the phenoxy adsorption.